Abstract
ObjectiveNI margins have to be chosen appropriately to control the risk of degradation of treatment effects in non-inferiority (NI) trials. We aimed to study whether the current choice of NI margins protects sufficiently against a degradation of treatment effect on an average.Study Design and SettingNI trials reflecting current practice were assembled and for each trial, the NI margin was translated into a likelihood of degradation. The likelihood of degradation was calculated as the conditional probability of a treatment being harmful given that it is declared non-inferior in the trial, using simulation. Its distribution among the NI trials was then studied to assess the potential risk of degradation.ResultsThe median (lower/upper quartile) NI margin among 112 binary outcome NI trials corresponded to an odds ratio of 0.57(0.45, 0.66), while among 38 NI trials with continuous outcome, to a Cohen’s d of −0.42(−0.54, −0.31) and a hazard ratio of 0.82(0.73, 0.86) among 24 survival outcome NI trials. Overall, the median likelihood of degradation was 56% (45%, 62%).ConclusionOnly two fifths of the current NI trials had a likelihood of degradation lower than 50%, suggesting that, in majority of the NI trials, there is no sufficient protection against degradation on an average. We suggest a third hurdle for the choice of NI margins, thus contributing a sufficient degree of protection.
Highlights
Non-inferiority (NI) trials have gained popularity over the years [1]
The median NI margin among 112 binary outcome NI trials corresponded to an odds ratio of 0.57(0.45, 0.66), while among 38 NI trials with continuous outcome, to a Cohen’s d of 20.42(20.54, 20.31) and a hazard ratio of 0.82(0.73, 0.86) among 24 survival outcome NI trials
Only two fifths of the current NI trials had a likelihood of degradation lower than 50%, suggesting that, in majority of the NI trials, there is no sufficient protection against degradation on an average
Summary
Though there are research areas where NI trials are not acceptable as a proof of efficacy for drug approval [2,3,4], NI trials are gaining importance in certain fields, as they are today a standard part of drug approval [5]. The aim of a NI trial is to show that a new treatment is not inferior to the standard treatment below a certain pre-specified margin called non-inferiority margin. Choice of this NI margin is a critical step in conducting NI trials. The narrower of the two margins should be used [8]
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