Randomized clinical trials (RCTs) are an essential method of evaluating health care interventions and a cornerstone for evidence-based health care. Their conduct, in particular for investigator-initiated RCTs, has long involved many practical challenges, challenges that have become increasingly complex and costly. Efforts to render RCTs more cost-effective are, therefore, urgently needed. Identifying lever-points for cost reductions requires knowledge of cost structures and cost drivers (e.g. recruitment duration, sample size, therapeutic area, number of trial sites). The medical literature, however, currently lacks detailed empirical data addressing costs and resource use of investigator-initiated RCTs as well as information about current practices of budget planning and cost monitoring, attitudes, needs, and preferences of trial investigators, trial support organizations (e.g. Clinical Trial Units), and funding agencies. Academic investigators usually depend on scarce financial resources; user-friendly and reliable tools to effectively limit costs of RCTs through optimized budget planning and cost monitoring during the conduct of an RCT are currently unavailable and sorely needed. We therefore propose three complementary projects using mixed-methods to render investigator-initiated RCTs more affordable and efficient through evidence-based budget planning, stakeholder consensus regarding relevant budget items, and the development of suitable tools. In Project A we will gather empirical resource use and cost data from 180 investigator-initiated RCTs in Switzerland, Germany, Canada, and the United Kingdom to investigate cost patterns, empirically identify major cost drivers and lever-points for cost savings, examine planned versus actual RCT costs, and explore heterogeneity of costs across medical fields and countries. Project B will consist of semi-structured interviews to explore current practices, attitudes, needs, and preferences of trial investigators, trial funders, and trial support organizations with respect to budget planning, funding acquisition for RCTs, managing costs during RCT conduct, and supporting tools in Switzerland. In Project C we will develop reliable and user-friendly budget calculation and cost monitoring tools for RCTs with stakeholder consensus based on systematically collected evidence from the literature/internet and informed by user needs and preferences (as elicited in Project B). We will formally user-test and evaluate the reliability and accuracy of developed tools using the generated database of empirical RCT cost data from Project A. The results of the proposed mixed-methods work will have immediate impact on the research practice of trial investigators, trial support organizations, and funders of RCTs in Switzerland and abroad. Given the increasing costs and complexity of RCTs, our project is timely and should shift the discussion from “rough guesses” to “analysing transparent and valid data” so that costs of clinical trials can be assessed, cost drivers identified, and costs effectively limited so that RCTs, critical to advancing clinical science, become more affordable.