Placebo comparisons are universally used in randomised controlled trials as a critical way to measure the safety and efficacy of new drugs and treatments. But increasingly, placebo controls are being used to assess surgical interventions, raising questions around ethics, risk to patients, and whether their design adds to scientific knowledge.
"The placebo used to evaluate a surgical intervention might involve close replication of the normal surgery, but may have some (or all) of the theoretically beneficial aspects taken away." said David Beard, Professor of Musculoskeletal and Surgical Science at NDORMS. "This is a relatively new, and sometimes controversial, way of evaluating surgery with some special considerations. Placebo interventions have all the potential risks of surgery (which thankfully are low) but with fewer perceived benefits - the methodology and ethical considerations for any such trial are therefore very important. We were keen to provide an up-to-date knowledge resource on all aspects of their use for the ongoing evaluation of some surgical procedures."
The Review, Considerations and methods for placebo controls in surgical trials, outlines what a placebo control entails and explains the present understanding of this approach in the context of surgery. It considers 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.
The work culminated in the production of practical guidance for researchers: Applying Surgical Placebo in Randomised Evaluations (ASPIRE). The ASPIRE guidelines are designed as a checklist for researchers to ensure that surgical placebo controls in randomised trials meet quality standards in rationale and ethics, design, conduct, and interpretation.
The insights in the Review are mainly based on the outputs of a workshop funded by the UK's National Institute of 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.
The Review concludes that surgical placebo controls in RCTs are not appropriate for all evaluations of surgery. They 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 of ethical issues, these trials need to have the greatest possible chance of answering the primary research question in a robust manner," said David. "Using the ASPIRE checklist, researchers can ensure they design trials that reach a minimum standard and mitigate any risks associated with the placebo surgical control."