Placebo controls in surgical trials

62 Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy 63 of surgical interventions. The aim of this paper is to provide a summary of current knowledge on 64 placebo controls in surgical trials. 65 A placebo control is a complex type of comparison group and, although powerful, presents many 66 challenges in a surgical setting. This review outlines what a placebo-surgical control entails and our 67 understanding of the placebo phenomenon in the context of surgery. It considers when placebo68 surgical controls are acceptable (and when they are desirable) in terms of ethical arguments and 69 regulatory requirements, how a placebo-surgical control should be designed, how to identify and 70 mitigate risk for participants in placebo surgical trials, how such trials should be conducted and 71 interpreted. 72 Use of placebo control is justified in randomised controlled trials of surgical interventions provided 73 there is a strong scientific and ethical rationale. Surgical placebos may be most appropriate where 74 there is poor evidence on the efficacy of the procedure and a justified concern that results of a trial 75 would be associated with high risk of bias, particularly due to the placebo effect. Feasibility work is 76 recommended to optimise RCT design and conduct. This review forms an outline for best practice 77 and provides guidance, in the form of the ASPIRE (Applying Surgical Placebo in Randomised 78 Evaluations) checklist, for those considering the use of a placebo-control in a surgical randomised 79 controlled trial. 80 INTRODUCTION & BACKGROUND 81 Compelling evidence of efficacy and safety should underpin all routine clinical therapies, ideally 82 based on data from randomised controlled trials (RCT), and surgical therapies are no exception. 83 Whilst an RCT comparing surgical treatment to no surgical treatment provides evidence of overall 84 efficacy, it fails to account for certain biases, especially placebo. These potential biases are 85