INTRODUCTION:
South Africa is a leading hub for clinical trials in Africa, with established research infrastructure and a diverse population. Nonetheless, the clinical trials ecosystem faces systemic, operational, and ethical challenges affecting the quality, feasibility, and relevance of randomised controlled trials (RCTs). This study examined stakeholder perceptions of these challenges, with particular attention to randomisation practices and the principles underpinning the Good Clinical Trials Collaboration (GCTC) guidance.

METHODS:
A convergent parallel mixed-methods design was employed where 9 workshops were conducted with 115 participants. Quantitative data were collected through pre-, post-, and follow-up workshop surveys administered face to face and virtually to participants involved in clinical trials. Qualitative data were generated through semi-structured in-depth interviews with 22 key stakeholders. Quantitative and qualitative data were analysed concurrently and integrated to provide a comprehensive understanding of the challenges affecting trial design, implementation, and conduct in South Africa.

RESULTS:
Participants reported multiple, interrelated challenges across the clinical trials continuum, including rushed protocol development, poorly defined endpoints, inadequate staff training, regulatory delays, infrastructure constraints, and financial instability. Recruitment and retention were affected by limited community awareness, mistrust, language barriers, and complex consent processes. Specific challenges related to randomisation included inadequate concealment, poor understanding of randomisation among participants, stringent eligibility criteria, and difficulties with adherence to allocated treatment arms. These challenges were particularly pronounced in rural resource-limited settings and in multi-site trials.

CONCLUSIONS:
Although South Africa remains a continental leader in clinical research, persistent systemic and contextual barriers undermine the scientific rigour, ethical integrity, and social relevance of clinical trials. Addressing these challenges requires coordinated reforms, including quality-by-design approaches, strengthened training and capacity building, streamlined regulatory processes, resilient infrastructure, and sustained community engagement. Embedding GCTC principles throughout trial planning and implementation is essential to ensuring robust, equitable, and contextually appropriate clinical trials in South Africa.