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

Abstract

Introduction 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. Methods 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. Results 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. Conclusion 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.

Keywords

Zelen design / real-world study / clinical study / traditional Chinese medicine / methodology / pragmatic clinical trial

Funding

This work was supported by the Backup Leader Support Program of Beijing University of Chinese Medicine (grant no.: 90010960920033); the Double First-Class Construction Support Program, Key Discipline of Traditional Chinese Medicine Evidence-Based Medicine of Beijing University of Chinese Medicine, Evidence-Based Medicine in Traditional Chinese Medicine (grant no.: 90010951310169); the Beijing Municipal Science and Technology Rising Star Program Cross-Disciplinary Project (grant no.: 20240484546); and the National Natural Science Foundation of China (grant no.: 82374298).

Author Contribution Statement

Ya-qian Wen: Data curation, methodology, formal analysis, and writing - original draft. Kai Liu: Data curation, methodology, and validation. Ying Zhang: Data curation, investigation, validation, and writing - original draft. Xiao-han Zhang: Methodology, writing - review & editing, and validation. Ting-xiu Liu: Formal analysis, validation, and writing - review and editing. Tae-Hun Kim: Methodology and writing - review & editing. Ze-yang Shi: Investigation and writing - review and editing. Yi-ke Song: Writing - review and editing. Zhao-lan Liu: Conceptualization, funding acquisition, supervision, project administration, and writing - review and editing.

Declaration of Competing Interest

The authors have no competing interests to declare that are relevant to the content of this article.

Data Availability

Additional data related to this paper may be obtained from the corresponding author upon reasonable request.

Use of AI Statement

None.

References

[1] Jia YL, Yao MH, Xu JY, et al. Exploring the application of Zelen design in real-world studies. Chin J Evid Based Med. 2022; 22(5):615-620.

[2] Sun X, Tan J, Tang L, et al. Revisiting real-world study. Chin J Evid Based Med. 2017; 17(2):126-130.

[3] Huang ZS, Luo YT, Liu JL. Method and practice of real world study. J Evid Based Med. 2014; 14(6):364-368.

[4] Zhang YL, Jin AM, Pan YS. Pragmatic clinical trials: a randomized trial in real-world studies. Chin J Stroke. 2022; 17(12):1299-1303.

[5] Tian F, Xie YM. Real-world study: a potential new approach to effectiveness evaluation of traditional Chinese medicine interventions. J Chin Integr Med. 2010; 8(4):301-306.

[6] Center for Drug Evaluation, National Medical Products Administration. Notice of the center for drug evaluation of the national medical products administration on issuing the guideline for communication and exchange on real-world evidence to support drug registration applications (trial) (No. 6, 2023). https://www.cde.org.cn/main/news/viewInfoCommon/8b59a85b13019b5084675edc912004f1. Accessed October 26, 2025.

[7] Lin R, Lin T, Lu XK, et al. Progress of Zelen’s design and its application value in clinical research. Chin J Evid Based Med. 2025; 25(9):1071-1077.

[8] Zhou TT, Zuo JX, Wang H, Liao X, Hu J. Strategies for overcoming enrollment challenges of patients in control group in randomized controlled trials of traditional Chinese medicine. China J Chin Mater Med. 2025; 50(7):1980-1986.

[9] Liu JP. Concept and method of randomization in clinical trials. Chin J Integr Tradit West Med. 2003; 23(4):244-246.

[10] Simon GE, Shortreed SM, DeBar LL. Zelen design clinical trials: why, when, and how. Trials. 2021; 22(1):541.

[11] Zelen M. A new design for randomized clinical trials. N Engl J Med. 1979; 300(22):1242-1245.

[12] Torgerson DJ, Roland M. What is Zelen’s design. BMJ. 1998; 316(7131):606.

[13] Zelen M. Randomized consent designs for clinical trials: an update. Stat Med. 1990; 9(6):645-656.

[14] Stott DJ, Langhorne P, Rodgers H. Informed consent. Two stage randomisation and consent would overcome many problems. BMJ. 1997; 315(7102):253.

[15] Hamajima N, Yuasa H, Nakamura M, Tajima K, Tominaga S. Nested consent design for clinical trials. Jpn J Clin Oncol. 1998; 28(5):329-332.

[16] McNulty C, Ricketts EJ, Rugman C, et al. A qualitative study exploring the acceptability of the McNulty-Zelen design for randomized controlled trials evaluating educational interventions. BMC Fam Pract. 2015; 16(1):169.

[17] Zeng L, Zhang H, Zhao YM. Introduction to Zelen’s design. In Proceedings of the 20th National Conference on Integrated Chinese and Western Medicine. Beijing, China; 2016: 71.

[18] Sun P, Li J, Fan WJ, et al. Effect of zelen’s Guige Lingxian decoction combined with moxibustion at neck Jiaji acupoint in treatment of cervical spondylotic radiculopathy of wind-cold-dampness arthralgia syndrome. Chin J Exp Tradit Med Form. 2020; 26(9):58-63.

[19] Liu ZQ. Clinical Efficacy Observation and Rs-Fmri Study on the Acupuncture Treatment of Perennial Allergic Rhinitis (AR) Based on Zelen’s Design [master’s thesis]. Chengdu, China: Chengdu University of Traditional Chinese Medicine; 2018.

[20] Xiang N. Based on Zelen’s Design to Observe the Clinical of Acupuncture on the Treatment of Perennial Allergical Rhinitis and the Influence on Serum Total Ige, Il-4 [master’s thesis]. Chengdu, China: Chengdu University of Traditional Chinese Medicine; 2018.

[21] Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals. International Committee of Medical Journal Editors Web site. https://www.icmje.org/icmje-recommendations.pdf. Accessed October 18, 2025.

[22] Homer CSE. Using the Zelen design in randomized controlled trials: debates and controversies. J Adv Nurs. 2002; 38(2):200-207.

[23] National Archives and Records Administration. Code of Federal Regulations. General requirements for informed consent. https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46/subpart-A/section-46.116#p-46.116(d). Accessed October 23, 2025.

[24] National Health Commission of the People’s Republic of China. Ethical review measures for ethical review of life science and medical research involving human being. Chin Pract J Rural Doctor. 2023; 30(3):1-7.

[25] Wittes J, Sample size calculations for randomized controlled trials. Epidemiologic Rev. 2002; 24(1):39-53.

[26] Angrist JD, Imbens GW, Rubin DB. Identification of causal effects using instrumental variables. J Am Stat Assoc. 1996; 91(434):444-455.

[27] Martin RM, Donovan JL, Turner EL, et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial. JAMA. 2018; 319(9):883-895.

[28] Terza JV, Basu A, Rathouz PJ. Two-stage residual inclusion estimation: addressing endogeneity in health econometric modeling. J Health Econ. 2008; 27(3):531-543.

[29] Dukes O, Vansteelandt S. A note on G-estimation of causal risk ratios. Am J Epidemiol. 2018; 187(5):1079-1084.

[30] Vink G. Roderick J. Little and Donald B. Rubin: statistical analysis with missing data. Psychometrika. 2022; 87:1575-1578.

[31] Ford I, Norrie J. Pragmatic trials. N Engl J Med. 2016; 375(5):454-463.

[32] Relton C, Torgerson D, O’Cathain A, Nicholl J. Rethinking pragmatic randomized controlled trials: introducing the “cohort multiple randomized controlled trial” design. BMJ Br Med J. 2010;340:c1066.

[33] Wang DL, Ji ZC, Hu HY, et al. Summary and evaluation of clinical research on the treatment of type 2 diabetes mellitus with Chinese patent medicine. Tianjin J Tradit Chin Med. 2023; 40(1):57-62.

[34] National Administration of Traditional Chinese Medicine. Notice of the national administration of traditional Chinese medicine on issuing the action plan for standardization of traditional Chinese medicine (2024-2026). http://www.natcm.gov.cn/fajiansi/zhengcewenjian/2024-07-30/34574.html. Accessed October 27, 2025.

[35] Dai XY, Zi MJ, Yang QN, Zhang WT, Qian ZZ, Gao R. Analysis and reflection on the literature status of TCM clinical research outcome indicators. J Tradit Chin Med. 2022; 63(12):1122-1127.

[36] Project Group of Traditional Chinese Medicine Guideline for Diagnosis, Treatment of Chronic Heart Failure, China Association of Chinese Medicine. Traditional Chinese medicine guideline for diagnosis and treatment of chronic heart failure (2022). J Tradit Chin Med. 2023; 64(7):743-756.

[37] Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019; 114(3):384-413.

[38] Chen XL, Liu FB, Mo CW, et al. The introduction and evaluation of patient preference randomized controlled trials. Tianjin J Tradit Chin Med. 2016; 35(1):64-68.

[39] Li XL, Zhang YJ, Liu JP, Cao HJ. Design and application of partial randomized clinical trials considering patients’ preferences in effect evaluation of Chinese medicine non-drug therapy. J Tradit Chin Med. 2016; 57(20):1750-1753,1767.

[40] Kong C, Chen X, Chen CX, Dong FX, Zhang XC. Research progress on the application of traditional Chinese health keeping exercise in prevention of falls in elderly. Chin Nurs Res. 2023; 37(22):4060-4065.