Elsevier

The Lancet

Volume 395, Issue 10226, 7–13 March 2020, Pages 828-838
The Lancet

Review
Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines)

https://doi.org/10.1016/S0140-6736(19)33137-XGet rights and content

Summary

Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial.

Introduction

Compelling evidence of efficacy and safety, ideally based on data from randomised controlled trials (RCTs), should underpin all routine clinical therapies, and surgical therapies are no exception. Although an RCT comparing surgical treatment to no surgical treatment provides evidence of overall efficacy, this comparison does not account for specific biases, especially the placebo effect. These potential biases are particularly likely for surgical interventions, where placebo effects have been shown to have substantial magnitude and duration, often amplified by the particular context of surgical care.1, 2 A surgical placebo control can be used to minimise bias but its use can be controversial as this control poses potential risk to the patient with little potential benefit and presents ethical, design, and trial conduct challenges.

Reviews of placebo-controlled surgical trials2, 3, 4 have included their use, issues of recruitment and feasibility, and effect on outcome and serious adverse events.5, 6 These reviews have not, however, explicitly considered issues of trial design, such as the definition and content of placebo, when it is appropriate to use (or not use) a placebo control in a surgical trial, factors that should guide the choice of a placebo design, and the influence of that choice on intervention standardisation. Some information on the ethical implications of surgical placebo trials has been published.7, 8, 9, 10, 11, 12

This Review aims to provide up-to-date knowledge on all aspects of placebo controls in the evaluation of surgery. The insights are mainly based on the outputs of a workshop funded by the UK's National Institute for Health Research and Medical Research Council, which brought together an international team of interdisciplinary experts (with research experience in placebo surgery) and patients. The workshop included a systematic update of important literature, an in-depth discussion of case studies, and an explanation of direct experience and best practice. This work culminated in the production of practical guidance for researchers: the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) checklist. In this Review, we have restricted our focus to studies of adults with capacity to consent to participate in surgical research.

Section snippets

Understanding the placebo context

Knowledge of the placebo effect is dominated by two main psychological theories, both of which apply to surgery. These theories are broadly labelled as conditioning, a learning theory in which placebo effects are underpinned by associative learning with the placebo paired with an active treatment to trigger a physiological response, and response expectancy, in which the placebo effects are underpinned by the patient's conscious or unconscious expectation that the placebo will have a particular

When are surgical placebo controls acceptable?

Surgical placebos might be most appropriate when there is poor evidence on the efficacy of the procedure and a justified concern that the results of an open trial would be associated with high risk of bias.

Ethical considerations are fundamental to the decision to use a surgical placebo control. Patients participating in a placebo-controlled surgical trial are at risk of a surgical intervention that does not have the presumptive causally effective element (ie, the essential surgical element).

Identifying and mitigating risk in placebo surgical trials

The ethics literature on the use of placebo surgical controls stresses the need for any potential risk from use of a placebo to be mitigated. The evidence on risk is mixed. The review by Wartolowska and colleagues3 found that surgical placebo-controlled trials did not appear to carry any greater risk than any other treatment or control group. However, most of the placebo RCTs in that review only evaluated endoscopic or minimal access interventions. A review from the Study Center of the German

Nomenclature for patients

The nomenclature for patients in surgical placebo trials is important and patient representatives are uneasy with descriptors such as deception and sham for surgical evaluation.44 Although such terms might often be seen in a scientific or trial design context, they are less acceptable to patients because of their negative connotations and should be avoided. Reporting guidelines under TIDieR (Template for Intervention Description and Replication) are being updated for placebo control (J Howick,

Interpretation and translation into change of policy and practice

In more than half of the placebo-controlled trials of surgery reported in peer reviewed literature, the results have shown no benefit of the definitive procedure compared with the placebo control.3 In many others, the placebo effect remains strong but is accompanied by a small, genuine treatment effect from the procedure. The presence of some effect from the index procedure is not surprising because of the ethical and academic justifications required for the use of a surgical placebo control.

Key messages

Our Review has described how placebo controls might justifiably be used in RCTs of surgical interventions, provided that there is a strong scientific and ethical rationale for the study. A surgical placebo control is not appropriate for all evaluations of surgery but might be best reserved for operations associated with low surgical complication risk, potentially low efficacy, unjustified usage, and in which a clinically significant placebo response is expected. In expectation of a complex set

Search strategy and selection criteria

Articles reporting randomised controlled trials (including long-term follow-ups and protocols) comparing an invasive procedure with a placebo procedure in living humans were included. Pilot randomised controlled trials retrieved by the review update search were included as a source of potentially useful information about methods. Interventional procedures that change the anatomy and require a skin incision or the use of endoscopic techniques were included. Placebo referred to a surgical

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