Six-part framework aims to clarify clinical trial outcomes

Researchers have developed a six-element framework intended to help investigators define clinical trial outcomes completely and consistently. The guidance specifies that an outcome should include its domain, a specific measurement, a specific metric, a cutoff when applicable, a variable type and a time point. The study reported that this structure can help readers determine whether outcomes were prespecified and whether different trials assessed the same outcomes.

The framework was developed through a methodological process that began with a review of relevant literature. The researchers created preliminary guidance, then refined it through pilot testing. They randomly selected 225 randomized controlled trials from ClinicalTrials.gov, where they evaluated 3,424 outcomes.

Two raters followed a structured approach to defining each outcome. When they encountered an outcome that the draft guidance could not define, the researchers revised the guidance and repeated the process until no further changes were required. The final version was produced through multiple drafts and discussions among the authors.

One major revision separated what the earlier framework called the “method of aggregation” into two distinct elements: variable type and cutoff. The variable type indicates whether the value for each individual is continuous or categorical. Cutoff applies when relevant to the outcome and is described in greater detail through three sub-elements.

The authors also expanded prior work on naming specific measurements for both subjective and objective outcomes and developed more comprehensive categories for specific metrics. These changes are intended to make outcome definitions more precise while maintaining consistency with the estimand framework. The resulting guidance is designed for use by trialists and sponsors in trial registrations, protocols and results reports.

Its six elements provide a common structure for describing outcomes across different stages of a trial’s documentation. Instead, it presents and tests a definition-building approach, using 225 trials and 3,424 outcomes as its pilot-testing sample.

Subject of Research: A six-element framework for defining outcomes in randomized controlled trials

Article Title: Guidance for defining outcomes in clinical trials

Article References: Ying, X., Li, T., McKenzie, J. E., Page, M. J., Ninan, K., Oberste, J.-P., Vorland, C. J., Brown, A. W., Qureshi, R., DeVito, N. J., Saldanha, I. J., Offringa, M., Butcher, N. J., Zhang, S., Nguyen, P.-Y., Menke, J., Lai, V. K. W., Kilicoglu, H., & Mayo-Wilson, E. (2026). Guidance for defining outcomes in clinical trials. PLOS Medicine, 23(10), e1005275. https://doi.org/10.1371/journal.pmed.1005275

Image Credits: AI Generated

DOI: 10.1371/journal.pmed.1005275

Keywords: clinical trials, outcome definitions, randomized controlled trials, reporting bias, trial protocols, estimands, ClinicalTrials.gov, research methodology, trial registration, Guidance, defining, outcomes