Non-inferiority trials: methodological and regulatory challenges

Background: A non-inferiority (NI) trial is intended to show that the effect of a new treatment is not worse than the comparator. We conducted a review to identify how NI trials were conducted and reported, and whether the standard requirements from the guidelines were followed. Methodology and Principal Findings: From 300 randomly selected articles on NI trials registered in PubMed at 5 February 2009, we included 227 NI articles that referred to 232 trials. We excluded studies on bioequivalence, trials on healthy volunteers, non-drug trials, and articles of which the full-text version could not be retrieved. A large proportion of trials (34.0 %) did not use blinding. The NI margin was reported in 97.8 % of the trials, but only 45.7 % of the trials reported the method to determine the margin. Most of the trials used either intention to treat (ITT) (34.9 %) or per-protocol (PP) analysis (19.4 %), while 41.8 % of the trials used both methods. Less than 10% of the trials included a placebo arm to confirm the efficacy of the new drug and active comparator against placebo, and less than 5.0 % were reporting the similarity of the current trial with the previous comparator’s trials. In general, no difference was seen in the quality of reporting before and after the release of the CONSORT statement extension 2006 or between the high-impact and lowimpact journals. Conclusion: The conduct and reporting of NI trials can be improved, particularly in terms of maximizing the use of blinding, the use of both ITT and PP analysis, reporting the similarity with the previous comparator’s trials to guarantee a valid constancy assumption, and most importantly reporting the method to determine the NI margin.