Access to Care and Self-Rated Health Status: Comparison of Rural and Urban Immigrants in the US.

In a randomized controlled trial (RCT) for a condition with an already established effective treatment, a placebo-controlled trial for a newly proposed therapy can be unethical. Patients randomized to placebo could be denied access to proven therapies. In such instances, non-inferiority trials can be employed to assess whether a new therapy is similar in efficacy to the current therapy, which is presumed or has been shown to be superior to placebo. Such non-inferiority trials with efficacy endpoints can indirectly support the new therapy’s superiority to placebo while allowing evaluation of other potential advantages in measured outcomes, such as lower cost or fewer adverse effects. However, when the existing therapy’s superiority to a placebo is less certain, a trial may incorporate both an active-control (to show non-inferiority) and placebo-control (to show superiority). On the contrary, non-inferiority trials can be designed primarily for safety endpoints which often involve direct comparison to placebo. Such trials hypothesize that the new proposed therapy will have no excess harm compared to the comparison. A less commonly discussed application of non-inferiority designs in RCTs involves cases where the current standard of care has not been proven superior to placebo. In such instances, particularly when concerns have been raised about the potential harm of the usual practice, a confirmatory trial may be warranted to test whether the placebo is non-inferior to the existing practice in efficacy. This approach essentially evaluates whether “doing nothing” results in outcomes no worse than the unproven intervention. Here, the placebo acts as the “new” therapy, deviating from the traditional model of comparing a novel active treatment to standard care or placebo. These “myth-busting” or deprescription-oriented studies are well suited for an RCT using a non-inferiority hypothesis and design. For example, older patients with confusion and positive urinalysis without any other infectious signs or symptoms are often given antibiotics, despite a lack of evidence supporting the superiority of such therapy over placebo. An RCT hypothesizing that the placebo arm (i.e. no antibiotics) would result in a non-inferior rate of delirium recovery in such a population compared to the antibiotic arm could potentially curb one of the most commonly cited reasons for inappropriate antibiotic use in the older population. Overall, there is limited discussion in the literature regarding the use of a placebo in trials where the placebo is compared to other therapy with non-inferiority intent. Moreover, methodological details for incorporating placebo in non-inferiority RCTs remain poorly defined. A preliminary search of PubMed, the Cochrane Database of Systematic Reviews, the Open Science Framework, and JBI (formerly known as the Joanna Briggs Institute) Evidence Synthesis revealed no current or underway evidence syntheses on this topic.