How to Optimize Healthy Volunteer Screening and Enrolment in Clinical Trials: A Qualitative and Quantitative Approach to Evaluate Processes and Healthy Volunteers' Perceptions

Healthy volunteers (HVs) are essential for phase I trials, yet their recruitment and screening remain resource-intensive and ethically complex. High screening failure (SF) rates highlight the need to evaluate and understand all aspects of the enrolment processes. We analyzed SF patterns in a large German HV cohort and explored participants' motivations, risk perceptions, and expectations regarding trial participation and screening procedure. We retrospectively evaluated screening results from phase I trials (2012-2022) at Heidelberg University Hospital. Additionally, we performed a prospective mixed-methods assessment with semi-structured interviews and a questionnaire evaluating recruitment, informed consent (IC), motivation, and decision making, distributed to experienced volunteers of four trial sites (October 2024-August 2025). Across 30 phase I trials, 900 volunteers were screened with a SF rate of 31.9% (n = 287), mainly due to laboratory abnormalities, medical history of concern, and organizational issues. Results from five semi-structured interviews and the questionnaire survey (n = 196) showed an overall acceptable satisfaction with the IC process, but identified areas of improvement in weighting of topics and risk perception. Although financial compensation was voted as the most important motivation, the decision process is multifactorial and an interplay of compensation, organizational aspects, and expected risks. We identified trial characteristics that are modifiable to facilitate interest in trial participation and provide data-driven recommendations to improve the ethical, efficient, and operational conduct of phase I trials. Furthermore, the results underline the relevance of addressing public perceptions and misconceptions surrounding clinical trials to improve willingness to engage in early-phase research.