Strengthening causal inference from randomised controlled trials of complex interventions.

Area of Science:

• Clinical Trials Methodology
• Complex Interventions Research
• Biostatistics

Background:

• Randomised controlled trials (RCTs) for complex interventions present unique design and analytical challenges.
• Existing guidelines inadequately address issues of outcome multiplicity and statistical power in these trials.
• Minimizing false positive and false negative findings is crucial for reliable evidence generation.

Purpose of the Study:

• To provide updated guidance for conducting RCTs of complex interventions.
• To address the challenge of managing multiple outcomes while controlling statistical errors.
• To enhance the scientific rigor and evidence extraction from complex intervention trials.

Main Methods:

• Formulating three core principles for RCT design and analysis of complex interventions.
• Emphasizing the linkage of chosen outcomes to intervention intent and program theory.
• Advocating for explicit declaration and adequate statistical power for all primary outcomes.

Main Results:

• Proposed principles include: outcomes driven by intervention theory and linked to hypotheses, adequate outcome power, and pre-trial transparency.
• Management of outcome multiplicity should prioritize planning and interpretation over post hoc adjustments.
• Redefining primary outcomes as those relevant to intervention intent, declared, and powered, limiting confirmatory inference to these.

Conclusions:

• Current distinctions between primary and secondary outcomes are insufficient for complex intervention RCTs.
• Adherence to the proposed principles can improve the quality and interpretability of evidence from complex intervention trials.
• Explicitly defined, declared, and adequately powered primary outcomes are essential for confirmatory causal inference.