Analyzing noninferiority trials: it is time for advantage deficit assessment – an observational study of published noninferiority trials

Abstract

Abstract:The concept of noninferiority (NI) trials is based on a belief that the new therapy may potentially offer a benefit for the patient or society in spite of it having a slightly lower efficacy. We introduce advantage deficit assessment (ADA), a simple framework similar to the benefitrisk assessment in superiority trials. ADA balances the advantage gained against the deficit in efficacy on a two-dimensional plane. It requires that NI trials provide quantitative information on both the advantage as well as on efficacy on scales, which can be compared in a meaningful manner. From this perspective, we study the feasibility of ADA among a set of NI trials published in four major medical journals. Among 113 published NI trials, about half assessed and reported at least one claimed advantage. For most other studies, an assessment seems to be feasible if considered in the planning of the study. Many studies claiming noninferiority report a positive gain in advantage. These trials have the potential to demonstrate a significant net benefit in an ADA, substantially changing the final judgment of the study results. ADA seems promising as it overcomes the current limitation of NI trials to demonstrate "only" noninferiority and brings them back to the mainstream of superiority trials by aiming to demonstrate a positive net benefit. ADA seems to be feasible in the majority of NI trials.

Use of Mortality as an Endpoint in Noninferiority Trials May Lead to Ethically Problematic Conclusions

“…(analysis #1) Freedom from treatment failure 6.0 11.8 (6.0 to 17.6) G Behringer 34 (analysis #2) Freedom from treatment failure 6.0 4.0 (0.7 to 7.3) G Kaul 35 Cardiac death, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization 4.0 2.7 (0.78 to 4.5) G Bwakura-Dangarembizi 36 Hospitalization or death 3.0 6.0 (0.9 to 11.2) G Behringer 34 (Analysis #3) Freedom from treatment failure 6.0 15.7 (9.1 to 22.4) H Jindani 37 BUnfavorable response^(see text) 6.0 13.3 (6.5 to 20.0) H HIV human immunodeficiency virus, MI myocardial infarction, MRSA methicillin-resistant Staphylococcus aureus, NACCE net adverse cardiac and cerebral events, MACE major adverse cardiac event, VTE venous thromboembolism in mortality, even within the context of noninferiority, is ethically dubious and such findings should be a central consideration in the discussion of these studies and how their results may impact clinical practice. Gladstone and Vach previously have described a method they term the advantage deficit assessment (ADA) 40 where the loss of efficacy is explicitly compared to the secondary advantage gained. Utilizing such a method (even conceptually), one is forced to clarify what secondary advantage (ease of use, reduced cost, etc.)…”

Time to recognize three classes of non-inferiority trial margins

“…A design obstacle for balancing advantage trials is that it is difficult to determine the value of reduced efficacy with treatment B compared with A that is quantitatively equivalent in clinical value to the different type of advantage it provides. This obstacle can theoretically be overcome by translating the advantage of each treatment into a generic health-related utility value,13 but this approach is not often taken. Also, individual patients can differ in the values they place on the advantages of each treatment so that no single non-inferiority margin may exist.…”

On the use of comparison regions in visualizing stochastic uncertainty in some two‐parameter estimation problems

“…Indeed, many approaches in benefit-risk assessment consider a benefit-risk plane similar to the cost-effectiveness plane (Guo et al, 2010;Mt-Isa et al, 2014). Gladstone and Vach (2015) suggested to evaluate noninferiority trials by considering an advantage-deficit plane.…”