Non-adherence in non-inferiority trials: pitfalls and recommendations | The BMJ

Non-adherence in non-inferiority trials can affect treatment effect estimates and often increases the chance of claiming non-inferiority under the standard intention-to-treat analysis. This article discusses the implications of different patterns of non-adherence in non-inferiority trials and offers practical recommendations for trial design, alternative analysis strategies, and outcome reporting to reduce bias in treatment estimates and improve transparency in reporting. Randomised controlled trials that test for non-inferiority of the experimental arm are performed when a new treatment is compared with an established standard of care. Instead of being required to have superior clinical efficacy, the new treatment might be preferred for its improved safety, convenience, or reduced cost. These trials are increasingly prevalent because highly efficacious standard-of-care treatments have been established for many diseases, making demonstration of superiority against standard-of-care implausible and placebo controlled trials without any active comparators unethical to perform.12 A basic weakness of non-inferiority trials, compared with superiority trials, is that poor conduct of the trial or deviations from the protocol could result in false rejection of the null hypothesis that the experimental treatment is inferior. Most trials report that some participants do not adhere to their allocated treatment. Intention-to-treat analysis estimates the treatment effect accounting for this real world adherence pattern by comparing outcomes between groups of participants defined by their allocated treatment; it measures the effect of allocating a treatment on participant outcomes, instead of the actual effect of treatment (often called an effectiveness trial). If the primary research interest is the causal effect of assigning treatments, then this estimate is likely to be the most relevant. In other situations, the question of primary interest is the causal effect of the treatment itself. Because many patterns of non-adherence result in reduced observed differences between the comparison arms, there is a risk that relying on …

Non-adherence in non-inferiority trials can affect treatment effect estimates and often increases the chance of claiming non-inferiority under the standard intention-to-treat analysis. This article discusses the implications of different patterns of non-adherence in non-inferiority trials and offers practical recommendations for trial design, alternative analysis strategies, and outcome reporting to reduce bias in treatment estimates and improve transparency in reporting. Randomised controlled trials that test for non-inferiority of the experimental arm are performed when a new treatment is co