The Placebo Response in Double-Blind Randomised Trials Evaluating Regenerative Therapies for Parkinson's Disease: A Systematic Review and Meta-Analysis.

In the field of stem cell technologies, exciting advances are taking place leading to translational research to develop cell-based therapies which may replace dopamine releasing neurons lost in patients with Parkinson's disease (PD). A major influence on trial design has been the assumption that the use of sham operated comparator groups is required in the implementation of randomised double-blind trials to evaluate the placebo response and effects associated with the surgical implantation of cells. The aim of the present review is to identify the improvements in motor functioning and striatal dopamine release in patients with PD who have undergone sham surgery. Of the nine published trials, there was at the designated endpoints, a pooled average improvement of 4.3 units, with 95% confidence interval of 3.1 to 5.6 on the motor subscale of the Unified Parkinson's Disease Scale in the 'OFF' state. This effect size indicates a moderate degree of improvement in the motor functioning of the patients in the sham surgical arms of the trials. Four of the nine trials reported the results of 18F-Fluorodopa PET scans, indicating no improvements of dopaminergic nigrostriatal neurones following sham surgery. Therefore, while the initial randomised trials relying on the use of sham operated controls were justified on methodological grounds, we suggest that the analysis of the evidence generated by the completed and published trials indicates that placebo controlled trials are not necessary to advance and evaluate the safety and efficacy of emerging regenerative therapies for PD.

Evidence-Based Evaluation of the Ethics of Sham Surgery for Parkinson's Disease.

The stated purpose of sham or placebo surgery is to enable the implementation of surgical placebo-controlled trials (SPTs) for evaluating the safety and efficacy of surgical interventions. Exposing the participants to the burdens and harms of sham surgery has been justified on the grounds of the absolute necessity for controlling large placebo effects and observer bias, assumed to be associated with surgical procedures. In the present review, we argue that evidence obtained from SPTs of cellular therapies for the treatment of Parkinson's disease (PD) has failed to demonstrate either large and consistent placebo effects or decisive methodological advantages for relying on sham surgical controls. We outline several alternative assessment strategies and designs available to establish the efficacy of cellular therapies. It is concluded that the evidence evaluated in the present analysis indicated that use of sham surgery in the context of developing novel surgical procedures for PD is not necessary, and therefore, unethical under a utilitarian model.