The Ethics of Single Blind Trials

Abstract

double-blind, placebo-controlled trials have been extensively discussed in the medical literature.' By contrast, the ethical issues associated with singleblind, placebo-controlled trials have received relatively little attention.2 Single-blind trials raise many of the same ethical issues as do double-blind trials, but also raise some unique issues related to the blinding of research subjects but not investigators to treatment assignment. In this article I present an example of a single-blind trial similar to one encountered by our Institutional Review Board (IRB), discuss some of the ethical issues that such a trial presents, and make recommendations for weighing the risks, benefits, and harms associated with singleblind trials. Details of the trial have been masked to maintain IRB confidentiality protections. For the purposes of this discussion, a double-blind trial is defined as a study in which research subjects, the investigators, and the outcome assessors are blinded to treatment assignment, meaning that all of these individuals are unaware of which subjects are receiving the active intervention and which are receiving placebo.3 For some studies, investigators might also be the outcome assessors. A single-blind trial is defined as a study in which only the research subjects are blinded to treatment assignment.4 Thus, the research subjects are kept unaware of whether they are receiving the active intervention or placebo, but investigators and outcome assessors know this information throughout the trial. Although the term single blinding has also been used to refer to situations in which the research subjects and investigators are aware of treatment assignment but the outcome assessors are not,5 this design does not raise the same types of ethical issues as the design I refer to and will not be discussed further. I also focus on single-blind trials that in theory could be double-blinded, such as placebo-controlled pharmaceutical trials or device or sham-surgery trials that researchers could conduct as closedas well as open-label studies. Case Study Protocol he investigators presented our IRB with a protocol designed to determine whether an experimental drug would improve cognitive and behavioral performance in patients with a specific neurologic condition. Subjects meeting neurobehavioral and magnetic resonance imaging entry criteria would be randomized to receive the active experimental drug or placebo. However, the study was to be conducted open-label so that the investigators would be aware of who was receiving active drug or placebo throughout the trial, even though subjects would be kept unaware of their treatment assignment. Outcomes, which were to be measured by the investigators, included cognitive and behavioral function as assessed by survey instrument, cerebral blood flow as assessed by magnetic resonance imaging, and adverse events related to the study drug. In theory, such a trial could have been double blinded, with both investigators (who were also the outcome assessors) and research subjects rendered unaware of who was receiving the active drug and who was receiving placebo. However, the investigators chose a single blind design for safety reasons. They reasoned that single blinding would allow rapid detection of worsening neurobehavioral function and other adverse effects related to the study drug. They also reasoned that in a single-center trial with few investigators, constituting non-blinded safety monitors separate from the investigators would not be feasible. In their view, single blinding would be the optimal method for protecting subjects from harm. In a study such as this which involved an intervention of uncertain benefit being investigated under equipoise6 and randomizing some subjects to a no-treatment arm, there is no direct benefit to subjects. benefit of the research is the generation of scientifically valid knowledge to disturb equipoise and inform the treatment of future patients. As a result, study-design characteristics that improve scientific validity provide benefit to the research and make it more ethically justifiable.7 Doubleblind, placebo-controlled designs increase such scientific validity for two reasons: First, they protect against Paul S. Heckerling, The Ethics of Single Blind Trials, IRB: Ethics & Human Research 27 No. 4 (2005): 12-16.