Strengthening tuberculosis clinical trial implementation: operational challenges, lessons learned, and consensus recommendations from a Delphi study

Tuberculosis (TB) remains a major global public health challenge, and most TB clinical trials are conducted in high-burden settings where operational constraints—ranging from fragile infrastructure to complex regulatory landscapes—frequently undermine trial efficiency and data quality. Despite an expanding research pipeline, there is a lack of harmonized operational guidance to manage these recurring obstacles. This study aimed to identify key operational challenges in TB clinical trials, including trials of treatment regimens, diagnostics, and other TB-related interventions, and to develop consensus-based recommendations to strengthen their implementation, particularly within or in close coordination with public health systems. We conducted a modified electronic Delphi (e-Delphi) study in accordance with ACCORD reporting guidelines. Operational challenges were first identified through an international workshop involving experienced investigators, trial managers, laboratory specialists, and policy experts from the SMA-TB and ADVANCE-TB consortia. These insights were synthesized into seven operational domains, from which 14 draft recommendations were developed. An international, multidisciplinary expert panel evaluated the recommendations through an anonymized, structured consensus process. All 14 recommendations reached high consensus (87.5%–100% agreement) in a single Delphi round. The resulting roadmap comprises seven interrelated domains: (1) trial design and protocol flexibility; (2) proactive regulatory/ethical engagement; (3) participant-centered recruitment and retention; (4) standardized data collection and quality systems; (5) laboratory infrastructure and workforce resilience; (6) robust statistical analysis planning; and (7) transparent operational governance. Qualitative feedback emphasized the need for balancing methodological standardization with context-sensitive flexibility, particularly in crisis-affected, under-resourced, or politically unstable settings. This consensus-based roadmap consolidates field-derived experience into actionable operational recommendations to strengthen the resilience, efficiency, and ethical robustness of TB clinical trials, particularly in high-burden LMIC settings. By addressing structural and operational barriers that disproportionately affect resource-limited contexts, these recommendations are relevant to trialists, funders, regulators, and national TB programs seeking to improve equity, generalizability, and policy relevance of trial evidence. Wider adoption may support more timely and robust evaluation of new TB interventions and accelerate their translation into public health practice.