THE NEED FOR FURTHER GUIDANCE ON THE HANDLING OF MULTIPLE OUTCOMES IN RANDOMISED CONTROLLED TRIALS: A SCOPING REVIEW OF THE METHODOLOGICAL LITERATURE.

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

Study design and setting: A scoping review with bibliographic database searches including Embase, PubMed, and Web of Science up to 22 July 2022 was conducted. Inclusion criteria were articles that: (1) provide advice on 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 summarised using thematic analysis.

Results: Searches retrieved 1716 articles of which 123 were included. Eight additional articles were identified by the specific websites search. Six main subthemes on methodological recommendations for using MOCs were identified from 74 of 123 articles (60%): (1) need to pre-specify 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 co-primary and composite outcomes were also identified, including their features, analyses methods, reporting, and challenges. Statistical methods for analysing 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 non-regulatory setting, including complex interventions.