The need for further guidance on the handling of multiple outcomes in randomized controlled trials: a scoping review of the methodological literature

Abstract

Objectives

To review current methodological guidance for handling and reporting of multiple outcomes (MOCs) in randomized controlled trials (RCTs).

Study Design and Setting

A scoping review with bibliographic database searches including Embase, PubMed, and Web of Science up to January 16, 2025 was conducted. Inclusion criteria were articles that: (1) provide advice on the design, analysis, or reporting of RCTs using MOCs; and/or (2) discuss statistical approaches for handling MOCs in RCTs. Six specific websites were also checked for formal and reporting guidelines. Included articles were summarized using thematic analysis.

Results

Searches retrieved 1716 articles of which 123 were included with additional 25 articles from updated search. Eight additional articles were identified by the specific website search. Six main subthemes on methodological recommendations for using MOCs were identified from 74 of 123 articles (60%): (1) need to prespecify outcomes and analysis, (2) multiplicity adjustment, (3) power and sample size implications, (4) secondary outcomes multiplicity, (5) considerations of MOCs correlation, and (6) specific applications of MOCs. Recommendations on coprimary and composite outcomes were also identified, including their features, analyses methods, reporting, and challenges. Statistical methods for analyzing MOCs were discussed in 53 of 123 articles (43%), with the majority describing modifications of pre-existing statistical approaches.

Conclusion

Current recommendations on using MOCs in RCTs focus primarily on statistical considerations and trials of licensing drugs or medical devices. Areas for further methodological research and guidance include reporting of the rationale for the use and selection of MOCs in RCTs and considerations for trials undertaken in nonregulatory setting, including complex interventions.