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Trials Avoid High Risk Patients and Underestimate Drug Harms Jason Abaluck, Leila Agha & Sachin Shah Share X LinkedIn Facebook Bluesky Threads Email Link Working Paper 34534 DOI 10.3386/w34534 Issue Date December 2025 The FDA does not formally regulate representativeness, but if trials under-enroll vulnerable patients, the resulting evidence may understate harm from drugs. We study the relationship between trial participation and the risk of drug-induced adverse events for cancer medications using data from the Surveillance, Epidemiology, and End Results Program linked to Medicare claims. Initiating treatment with a cancer drug increases the risk of hospitalization due to serious adverse events (SAE) by 2 percentage points per month (a 250% increase). Heterogeneity in SAE treatment effects can be predicted by patient's comorbidities, frailty, and demographic characteristics. Patients at the 90th percentile of the risk distribution experience a 2.5 times greater increase in SAEs after treatment initiation compared to patients at the 10th percentile of the risk distribution yet are 4 times less likely to enroll in trials. The predicted SAE treatment effects for the drug's target population are 15% larger than the predicted SAE treatment effects for trial enrollees, corresponding to 1 additional induced SAE hospitalization for every 25 patients per year of treatment. We formalize conditions under which regulating representativeness of SAE risk will lead to more externally valid trials, and we discuss how our results could inform regulatory requirements. * Acknowledgements and Disclosures We are thankful to Daniel Park and Brendan Balthis for their expert research assistance. We are grateful for Christopher Manz and Hari Raman for their thoughtful guidance on how to classify oncology trials and identify trial-eligible cohorts in SEER-Medicare data. We thank David Chan and seminar participants at University of Massachusetts-Amherst for their helpful feedback on this project. Sachin Shah received grant funding from NIA K76AG074919 to support this work. The views expressed herein are those of the authors and do not necessarily reflect the views of the National Bureau of Economic Research. * Citation and Citation Data Copy Citation Jason Abaluck, Leila Agha, and Sachin Shah, "Trials Avoid High Risk Patients and Underestimate Drug Harms," NBER Working Paper 34534 (2025), https://doi.org/10.3386/w34534. 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