The ELECTRA Trial: Approach to Contemporary Challenges in the Development and Implementation of Double-Blinded,...

Background: Achieving evidence-based practice change in surgery has always been challenging, with many aspects of common clinical practice evolving through lower-level studies that are susceptible to bias and confounding rather than high-quality evidence. This challenge is even more pronounced in the setting of low-volume, high-complexity surgical oncology. Additionally, when the costs of interventions or technologies are high, designing and developing such studies within financially constrained national healthcare systems becomes even more complicated, potentially widening perceived healthcare inequalities between private and publicly funded systems. However, this is precisely the area where a lack of evidence can either hinder the development of significant new clinical advances or lead to the adoption of expensive and ineffective treatments. Here, we describe the novel approaches adopted in the design, development, and implementation of the ELECTRA trial, a randomised, controlled, double-blinded feasibility study with a planned extension to a late-phase trial. Methods: The Cancer Research UK ELECTRA (NCT05877352) trial is a three-armed randomised, controlled clinical trial designed to evaluate the incremental benefit of adding intraoperative electron beam radiotherapy (IOERT) to pelvic exenteration surgery for locally advanced and locally recurrent rectal cancer. ELECTRA is double-blinded, with patients, surgeons, and oncologists unaware of whether IOERT is administered or not. The primary feasibility outcome focuses on the ability to successfully recruit and randomise participants, while the subsequent primary outcome assesses IOERT field local control. Results: We describe the collaborative process involved in developing the trial, including national and international consultations to determine the best study design and the most optimal outcome measures to evaluate. We outline the extensive patient participation and input into the study design. Given the complexity and evolving nature of the field, with no clear international standardisations, we outline the processes used to address internationally agreed definitions, radiological standardisation, surgical learning curves, quality assurance, and pathological standardisation, as well as the broader impact and benefits of these activities. Finally, we describe the novel design utilised to facilitate the involvement of national and international units with varying levels of equipoise regarding IOERT. Conclusions: Historically, randomised clinical trials have not been the standard approach for evaluating surgical interventions due to their practical and methodological challenges, particularly in high-complexity, low-volume settings. Despite these difficulties, they remain the gold standard for evidence-based practice. The ELECTRA trial exemplifies a complex, innovative trial design that addresses an unmet need in a specialised area of high-complexity surgery. Using ELECTRA as an example, we highlight the genuine challenges in designing such complex trials and provide recommendations to facilitate the conduct of future well-designed surgical studies.