Editorial on hypothesis and objectives in clinical trials: superiority, equivalence and non-inferiority

Abstract

EditorialRandomized clinical trial is often considered as the Gold Standard method for comparing treatment effects. In practice, taking into consideration their main objectives, the majority of clinical trials are aimed to establish the superiority of an intervention regarding to an active control or placebo [1]. Within the methodological core of these so called superiority trials, the assessment of the statistical signification of the differences between or among interventions, and their clinical relevance, are both of main importance. Appropriate statistical tests to assess this superiority should be performed, with the null hypothesis being: the difference between treatments is equal to 0 (H0 = 0), and the alternative hypothesis: treatments are different -or, the difference between treatments is not equal to 0 (H1 0)(if two sided)-. The rejection of the null hypothesis is in the foundation of the methodological assessment of superiority [2]. The number of patients required to confront the hypotheses is inversely related to the expected between-treatment differences. The smallest the expected difference between two interventions, the highest the number of patients to be included into the trial. But, how to interpret a non-significant result obtained from a clinical study designed as a superiority trial? Does this mean that the interventions under study should be considered as equivalent?. Clearly, the answer is negative. From the methodological standpoint, the expression: we have no evidence of difference between treatments, should not be considered as equivalent to: we have evidence of no difference between interventions [3].Very often, the aim of a clinical trial is to show that a certain intervention is equivalent to or non inferior than another one. In this case, as stated before, a non-significant superiority testing should not be interpreted as a proof of no difference between treatments. Under an equivalence hypothesis, where the between treatments difference is assumed to be equal to 0, the calculation of a sample size following the rules established for superiority trials is impossible or in the best case (by employing an estimated difference close to 0) would result in an unrealistic extremely large number [1]. Instead, equivalence and non-inferiority trials should be conceived, planned and applied to these purposes. In general, neither equivalence nor non-inferiority should be definitively concluded from superiority trials exhibiting non-significant results.Improvements into the galenics of a formulation or a modification in a drug delivery system should not affect the pharmacokinetic (PK) profile of the drug. That is also the case for the comparison between the PK parameters of a generic preparation versus an original product. This is the rationale for the so called bioequivalence trials, the most frequent type of equivalence study. Being μ S the mean value for an specific PK indicator in the standard or the original product, and μ T the mean for the same parameter of the new product under testing,...

Phase III Trials of New Oral Anticoagulants in the Acute Treatment and Secondary Prevention of VTE: Comparison and Critique of Study Methodology and Results

“…All of the trials comparing a NOAC with VKAs were designed to assess for non-inferiority and utilized intention-to-treat analyses, but it is recommended to also perform a per-protocol analysis because this strengthens an equivalence finding if both analyses are in agreement [ 37 ]. The evidence for non-inferiority of NOACs may depend on the quality of VKA treatment reflected by TTR.…”