Non‐inferiority studies: is ‘better’ the enemy of ‘good enough’?

Imagine there is an established way of providing anaesthesia to a certain population of patients for a given procedure. A new and possibly better technique, drug or piece of equipment becomes available and a randomised controlled trial is undertaken to compare efficacy. This, although often never labelled as such, is a superiority trial with a null hypothesis of no difference between groups. Suppose the new technique, drug or piece of equipment has advantages other than clinical efficacy, such as reduced associated financial costs or improved ease of administration. In order to prove it is non-inferior to (or no worse than) standard practice, a non-inferiority randomised controlled trial is undertaken. This time, the null hypothesis states that standard practice is superior to the new treatment and the study is necessarily powered to reject the null hypothesis within a pre-defined margin of non-inferiority (Table 1). This margin is often termed D. Non-inferiority studies are an increasingly popular way to study and introduce a new treatment with comparable efficacy to standard care. The intent is not to demonstrate equivalence, but rather that the new treatment is no worse than the active control. In the past, non-inferiority trials of pharmacological agents such as antibiotics, antidepressants and cardiovascular medicines have attracted much criticism and discussion on the best way to conduct non-inferiority trials [1–3]. Concerns include: industry-sponsored trials of new agents not conferring additional benefits above an established treatment; the questionable ethics of enrolling patients in such studies; the use of intention to treat analyses [4]; the use of surrogate and composite outcomes [5]; selection of unreasonably high margins of inferiority (D); poor study conduct and reporting; and inadequate power calculations. Reviews of published non-inferiority trials have revealed only 24% describe the means by which D is chosen and 25% fail to incorporate D into the power calculation [6, 7]. Due to these concerns and a lack of guidance on noninferiority trial design and reporting, an extension to the CONSORT 2010 statement for non-inferiority studies was published in 2012 [8]. Selecting the value for the margin of inferiority, D, is the most crucial, challenging and controversial aspect of any non-inferiority study. If a large margin is selected, there is a risk of a type-1 error (i.e. incorrect rejection of a true null hypothesis) and therefore accepting a truly inferior new treatment as non-inferior to standard care. This could be disastrous for patients, especially if the outcome was of clinical significance, such as mortality. If a small margin is selected, the chance of an inconclusive finding is greater and many more participants will be required. The margin must, therefore, be selected as conservatively as possible through clinical, rather than statistical judgement, although how this should be decided upon in all circumstances remains unclear [9]. A common method to set the value of D is through the use of previous studies of standard care as a form of historical control, although the use of historical controls has its own well-described limitations [10], or even to consult meta-analyses to come up with an appropriate value for D. Nevertheless, in some cases, no studies are available to allow an estimation of D, leaving researchers with no option but to guess or propensity match, which presents a range of difficulties in this setting [11]. In a recent study published in Anaesthesia, Nakanishi et al. reported their non-inferiority trial comparing laryngeal morbidity and tracheal intubating conditions using the McGRATH MAC videolaryngoscope with or without neuromuscular blockade [12]. The use of a neuromuscular blocking agent (NMBA) is arguably not without risk, and their effect on postoperative laryngeal morbidity and tracheal intubating conditions when used with a videolaryngoscope is