Objectives To identify non-inferiority trials within a cohort where the experimental therapy is the same as the active control comparator but at a reduced intensity and determine if these non-inferiority trials of reduced intensity therapies have less favourable results than other non-inferiority trials in the cohort. Such a finding would provide suggestive evidence of biocreep in these trials.
Design This metaresearch study used a cohort of non-inferiority trials published in the five highest impact general medical journals during a 5-year period. Data relating to the characteristics and results of the trials were abstracted.
Primary outcome measures Proportions of trials with a declaration of superiority, non-inferiority and point estimates favouring the experimental therapy and mean absolute risk differences for trials with outcomes expressed as a proportion.
Results Our search yielded 163 trials reporting 182 non-inferiority comparisons; 36 comparisons from 31 trials were between the same therapy at reduced and full intensity. Compared with trials not evaluating reduced intensity therapies, fewer comparisons of reduced intensity therapies demonstrated a favourable result (non-inferiority or superiority) (58.3%vs82.2%; P=0.002) and fewer demonstrated superiority (2.8%vs18.5%; P=0.019). Likewise, point estimates for reduced intensity therapies more often favoured active control than those for other trials (77.8%vs39.7%; P<0.001) as did mean absolute risk differences (+2.5% vs −0.7%; P=0.018).
Conclusions Non-inferiority trials comparing a therapy at reduced intensity to the same therapy at full intensity showed reduced effects compared with other non-inferiority trials. This suggests these trials may have a high rate of type 1 errors and biocreep, with significant implications for the design and interpretation of future non-inferiority trials.
- clinical trials
- putative placebo effect
- non-inferiority trials
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Contributors SKA and AMH designed the study and performed data abstraction and analysis and drafting and reviewing the manuscript. MHS provided critical analysis of the design and analysis of the study and assisted with drafting and reviewing and revising the manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The dataset used for this manuscript may be obtained by contacting the corresponding author.
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