Recommendations for designing and analysing multi-arm non-inferiority trials: a review of methodology and current practice

Abstract

Background and purpose Multi-arm non-inferiority (MANI) trials, here defined as non-inferiority trials with multiple experimental treatment arms, can be useful in situations where several viable treatments exist for a disease area or for testing different dose schedules. To maintain the statistical integrity of such trials, issues regarding both design and analysis must be considered, from both the multi-arm and the non-inferiority perspectives. Little guidance currently exists on exactly how these aspects should be addressed and it is the aim of this paper to provide recommendations to aid the design of future MANI trials. Methods A comprehensive literature review covering four databases was conducted to identify publications associated with MANI trials. Literature was split into methodological and trial publications in order to investigate the required design and analysis considerations for MANI trials and whether they were being addressed in practice. Results A number of issues were identified that if not properly addressed, could lead to issues with the FWER, power or bias. These ranged from the structuring of trial hypotheses at the design stage to the consideration of potential heterogeneous treatment variances at the analysis stage. One key issue of interest was adjustment for multiple testing at the analysis stage. There was little consensus concerning whether more powerful p value adjustment methods were preferred to approximate adjusted CIs when presenting and interpreting the results of MANI trials. We found 65 examples of previous MANI trials, of which 31 adjusted for multiple testing out of the 39 that were adjudged to require it. Trials generally preferred to utilise simple, well-known methods for study design and analysis and while some awareness was shown concerning FWER inflation and choice of power, many trials seemed not to consider the issues and did not provide sufficient definition of their chosen design and analysis approaches. Conclusions While MANI trials to date have shown some awareness of the issues raised within this paper, very few have satisfied the criteria of the outlined recommendations. Going forward, trials should consider the recommendations in this paper and ensure they clearly define and reason their choices of trial design and analysis techniques.