US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer

Published:November 08, 2021DOI:


      • Many trials report “no meaningful difference” in health-related quality of life (HRQL) or function between arms despite observing notable differential toxicity. A possible explanation is that mean change from baseline analyses of function or HRQL can obscure important change in subgroups experiencing symptomatic toxicity.
      • In our case examples, for those patients who remained on treatment and completed patient-reported outcome assessments, there was a greater proportion of patients in the treatment arm reporting diarrhea. Patients reporting more frequent diarrhea reported lower physical functioning and global health status and quality of life than patients with no diarrhea, regardless of treatment arm.
      • When differential toxicity between arms is observed, additional exploratory analyses aided by data visualization that evaluate functioning or HRQL by symptomatic adverse event are needed. This information can further inform the safety and tolerability of the investigational agent under study.



      Many trials conclude “no clinically meaningful detriment” to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration.


      This study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months.


      Generally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms.


      In trials with moderate to large differences in symptomatic toxicity by arm, reporting “no meaningful difference in functioning and HRQL between arms” based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.


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