However, for many debilitating and life-threatening infectious diseases in LMICs, vaccines either do not exist, or they are insufficiently efficacious1 or unavailable to most of the population due to high cost. Many vaccines targeting diseases prevalent in LMICs are currently

under development. As investigators and sponsors plan large-scale clinical trials to test the safety and efficacy of these new vaccines, important ethical issues can arise in trial design, particularly around the use of a placebo control arm Gefitinib when an efficacious vaccine already exists. Randomised, placebo-controlled trials are widely considered the gold standard for evaluating the safety and efficacy of a new vaccine.

In these trials, participants are randomized to receive either the vaccine under investigation or a placebo (i.e. an inert substance, such as a saline injection). Randomisation and the use of placebo interventions are designed to control for confounding effects, such that significant differences in disease incidence or adverse effects between the vaccine and control groups can likely be attributed to the vaccine. However, randomised, placebo-controlled trial designs often raise ethical concerns when participants in the control arm are deprived of an existing vaccine. Furthermore, testing a new vaccine against Ku-0059436 solubility dmso placebo is scientifically and ethically fraught when the hypothesis being tested is whether an experimental vaccine is more efficacious than one already in use in the same or in other settings. Currently, there is insufficient and inconsistent guidance on how to evaluate the use of placebo controls in vaccine all trials. Most ethical guidelines for research do not address vaccine trials specifically; and, in those that do, the guidance regarding

placebo use is limited [2] and [3]. Moreover, general ethical guidelines for research – authored by both national and international bodies – offer conflicting guidance on the use of placebo controls [4], [5], [6], [7], [8], [9], [10] and [11]. Some guidelines call for exclusion of placebo use altogether when there is a proven or established effective intervention against the condition under study [10]. Others allow placebo use, provided the risks of withholding or delaying the existing intervention are either negligible or there are compelling methodological reasons for including a placebo arm in the trial [4], [5], [7], [8] and [9]. Yet, the level of risk deemed acceptable when there are compelling reasons for placebo use varies greatly. Most guidelines allow no more than minimal risks, excluding risks of serious or irreversible harm [4], [5] and [9] or allowing placebo use only in the case of self-limiting disease [7]. In contrast, others set no explicit risk limit in research that is relevant to the local population [8].