Clinical Trials

❘❙❚■ Chapter 14 | Noninferiority TrialsWhat is a noninferiority trial?Noninferiority trials aim to show that an experimental treatment is not worse thanan active control by more than a predefined noninferiority margin, which is oftendenoted by the symbol δ. This margin is the largest reduction in efficacy that can bejudged as clinically acceptable [1]. It is not the case that the lack of a statisticallysignificant difference in a superiority trial demonstrates noninferiority. From theoutset, the trial must be designed to conclusively show that the new treatment’seffect is worse by no more than an agreed, prespecified amount.A noninferiority trial is a specific type of trial known as an equivalence trial(see Chapter 12). For an equivalence trial, interest lies in whether the effect of thetwo treatments differs by more than the equivalence margin in either direction,and not solely in whether the new treatment is not worse. Care needs to be takenwith interpreting the terminology used – the term ‘equivalence’ is often used(incorrectly) when the trial’s aim is specifically noninferiority. It is usual for theterm noninferiority to be used in therapeutic studies and for equivalence to be usedin pharmacokinetic (such as ‘bioequivalence’) studies or in safety studies.The following study will illustrate issues relating to the design and analysis ofnoninferiority clinical trials.ExampleA randomized, double-blind, multicenter, parallel-group study was undertakento assess the efficacy and safety of oral Augmentin SR 2000/125 mg(pharmacokinetically enhanced amoxicillin/clavulanate) twice daily versus oralAugmentin 875/125 mg (amoxicillin/clavulanate) twice daily for 7 days in thetreatment of adults with bacterial community-acquired pneumonia (CAP) [2].The objective of this study was to demonstrate that, in adults, oral AugmentinSR 2000/125 mg is at least as effective clinically as oral Augmentin 875/125 mg inthe treatment of CAP in terms of clinical response (success/failure) at test of cureat 4 weeks posttreatment (primary endpoint). Further details of this study aresummarized in Table 1.Noninferiority trials are also used in other therapeutic areas. For example,an asthma trial might be conducted with bronchodilator drugs in order todemonstrate the noninferior efficacy of a novel delivery method in comparisonwith a conventional inhaler. A typical primary endpoint might be improvement inpeak expiratory flow, with a δ of –12 L/min.132