Applying the Zelen design to real-world studies in traditional Chinese medicine: feasibility, ethical considerations, and methodological challenges

In traditional Chinese medicine (TCM) clinical research, patients often have strong preferences for TCM therapies. In addition, non-pharmacological interventions such as acupuncture and tuina make effective blinding of patients and practitioners difficult, which may introduce Hawthorne effects and resentful demoralization. Conventional randomized controlled trials also face challenges, including poor recruitment, high dropout rates, and increased bias risk, which limit research efficiency and evidence quality. The Zelen design provides a promising methodological solution to these issues.

This study presents a methodological analysis of the Zelen design for TCM real-world studies, with three focal contributions: (Ⅰ) in-depth feasibility analysis of the Zelen design tailored to the complexities of TCM interventions; (Ⅱ) a simulated TCM trial including a worked example of complier average causal effect (CACE) analysis, with discussion of its idealized assumptions and the need for sensitivity analyses; and (Ⅲ) an in depth examination of ethical safeguards and statistical methods for managing contamination. Key considerations reviewed include trial registration, ethical requirements, sample size calculation, blinding, appropriate applications, and TCM-specific outcome measures.

This analysis identifies key barriers to broader implementation of the Zelen design for evaluating TCM efficacy evaluation, including ethical and regulatory uncertainty surrounding the randomization-before-consent process, a lack of dedicated methodological guidelines and statistical tools, and the inherent complexity of TCM interventions, which heightens contamination risk and complicates compliance definition, while also assessing the overall value of design. Despite these challenges, the Zelen design demonstrates clear advantages in improving patient recruitment and treatment adherence while preserving the benefits of randomization.

The Zelen design offers a balanced pathway that integrates scientific rigor with clinical practicality, and further refinement of design strategies tailored to TCM characteristics is warranted. Future efforts should prioritize methodological innovation and standardization to improve the overall quality of real-world studies in TCM.