Guidance for defining outcomes in clinical trials
12 affiliations
- 1Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America
- 2Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
- 3Methods in Evidence Synthesis Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- 4Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, United States of America
- 5Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
- 6Arkansas Children’s Research Institute, Little Rock, Arkansas, United States of America
- 7Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
- 8Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
- 9Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
- 10Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
- 11Department of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island, United States of America
- 12School of Information Sciences, University of Illinois Urbana-Champaign, Champaign, Illinois, United States of America
Abstract
Background: Defining outcomes completely before conducting clinical trials helps to mitigate concerns about reporting biases; however, there is limited guidance to help investigators define outcomes completely. Methods: Building on a previous framework, we developed guidance for defining trial outcomes completely and consistently. We reviewed literature, developed preliminary guidance, and refined guidance iteratively through pilot testing. We randomly selected 225 randomized controlled trials (RCTs) from ClinicalTrials.gov, which evaluated 3,424 outcomes. Two raters followed a structured approach to define each outcome. When raters encountered outcomes they could not define, we refined our guidance. We continued this process until no further changes were needed. We finalized the guidance through multiple drafts and discussions among authors. Findings: In clinical trials, a completely defined outcome includes six elements: outcome domain, specific measurement, specific metric, cutoff (if applicable), variable type, and time point. We developed guidance for naming specific measurements for both subjective and objective outcomes. We expanded on prior work by describing more comprehensive categories for specific metrics. To be consistent with the estimand framework, we replaced “method of aggregation” with two distinct elements that describe values in individuals (rather than summary measures): “variable type” and “cutoff.” We further defined “cutoff” with three sub-elements, and we defined “variable type” as whether the value for each individual is continuous or categorical. Conclusions: Trialists and sponsors could use this framework and guidance to define outcomes in trial registrations, protocols, and results reports. When all six elements are defined, readers can better determine whether reported outcomes were prespecified and whether different trials assessed the same outcomes. Why was this study done?: What did the researchers do and find?: What do these findings mean?: In this Guidelines and Guidance article, Xiangji Ying and colleagues provide updated guidance—including a six-element framework with worked examples—for defining outcomes completely and consistently in clinical trials.
Related
- Measuring mild cognitive impairment using routinely collected health-care data: A conceptual framework and guidance for embedded pragmatic clinical trials.
- Associations between behavioral intervention dose and outcomes in children and adolescents with obesity: meta-regression of randomized clinical trials
- Causal relationship between liver fat reduction and clinical outcomes in human genetic studies and randomized clinical trials of metabolic-dysfunction associated steatohepatitis
- Azacitidine-Venetoclax in Elderly and Unfit Acute Myeloid Leukemia: Real-World Outcomes Outside Clinical Trials.
- Post-acne Erythema: A Systematic Review of Randomized Controlled Trials on the Comparative Efficacy and Safety of Interventions Across Clinical, Instrumental, and Patient-Reported Outcomes.
BibTeX
@article{ying2026guidance,
title = {{Guidance for defining outcomes in clinical trials}},
author = {Xiangji Ying and Tianjing Li and Joanne E. McKenzie and Matthew J. Page and Kiran Ninan and Jean-Pierre Oberste and Colby J. Vorland and Andrew W. Brown and Riaz Qureshi and Nicholas J. DeVito and Ian J. Saldanha and Martin Offringa and Nancy J. Butcher and Sirui Zhang and Phi-Yen Nguyen and Joe Menke and Veronica Ka Wai Lai and Halil Kilicoglu and Evan Mayo-Wilson},
journal = {PLOS Medicine},
year = {2026},
month = oct,
doi = {10.1371/journal.pmed.1005275},
url = {https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005275},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Guidance for defining outcomes in clinical trials
AU - Xiangji Ying
AU - Tianjing Li
AU - Joanne E. McKenzie
AU - Matthew J. Page
AU - Kiran Ninan
AU - Jean-Pierre Oberste
AU - Colby J. Vorland
AU - Andrew W. Brown
AU - Riaz Qureshi
AU - Nicholas J. DeVito
AU - Ian J. Saldanha
AU - Martin Offringa
AU - Nancy J. Butcher
AU - Sirui Zhang
AU - Phi-Yen Nguyen
AU - Joe Menke
AU - Veronica Ka Wai Lai
AU - Halil Kilicoglu
AU - Evan Mayo-Wilson
PY - 2026
DA - 2026/10/21
JO - PLOS Medicine
DO - 10.1371/journal.pmed.1005275
UR - https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005275
AB - Background: Defining outcomes completely before conducting clinical trials helps to mitigate concerns about reporting biases; however, there is limited guidance to help investigators define outcomes completely. Methods: Building on a previous framework, we developed guidance for defining trial outcomes completely and consistently. We reviewed literature, developed preliminary guidance, and refined guidance iteratively through pilot testing. We randomly selected 225 randomized controlled trials (RCTs) from ClinicalTrials.gov, which evaluated 3,424 outcomes. Two raters followed a structured approach to define each outcome. When raters encountered outcomes they could not define, we refined our guidance. We continued this process until no further changes were needed. We finalized the guidance through multiple drafts and discussions among authors. Findings: In clinical trials, a completely defined outcome includes six elements: outcome domain, specific measurement, specific metric, cutoff (if applicable), variable type, and time point. We developed guidance for naming specific measurements for both subjective and objective outcomes. We expanded on prior work by describing more comprehensive categories for specific metrics. To be consistent with the estimand framework, we replaced “method of aggregation” with two distinct elements that describe values in individuals (rather than summary measures): “variable type” and “cutoff.” We further defined “cutoff” with three sub-elements, and we defined “variable type” as whether the value for each individual is continuous or categorical. Conclusions: Trialists and sponsors could use this framework and guidance to define outcomes in trial registrations, protocols, and results reports. When all six elements are defined, readers can better determine whether reported outcomes were prespecified and whether different trials assessed the same outcomes. Why was this study done?: What did the researchers do and find?: What do these findings mean?: In this Guidelines and Guidance article, Xiangji Ying and colleagues provide updated guidance—including a six-element framework with worked examples—for defining outcomes completely and consistently in clinical trials.
SN - 1549-1676
SN - 1549-1277
ER -