Background: Classical randomized controlled trials often meet difficulties in enrollment and compliance due to subjects’ preference for the randomization scheme. Zelen’s design can largely resolve these issues through randomizing subjects before informing stage.
Objectives: This study systematically reviewed the progress of Zelen’s design and its modifications in clinical research and clarified its methodological elements, advantages, and limitations.
Methods: A systematic literature search was conducted for Zelen’s design from the inception of databases (PubMed, Cochrane library, CNKI, WanFang, and Vip database) to February 2023. The data were extracted, including sample size, population characters, length of follow-up, Zelen’s model, group shifting, and statistical methods.
Results: One hundred twelve trials were included. The range of sample size was from 15 to 23,024. The longest follow-up length was 17.2 years. The dominant disease in this design was mental disorders (21, 18.75%), followed by osteoarthrosis diseases (16, 14.29%), cancer (11, 9.82%), cardiovascular diseases (10, 8.93%), and others. Regarding types of consent, more than half of the trials used a double-consent (57, 50.89%), 32 (28.57%) used a single-consent, and others did not report the consent procedure. Twelve trials (10.71%) used a modified Zelen’s design nested within an observational study. This design used a two-stage informed consent. Stage 1, patients were invited to participate in a cohort study; Stage 2, patients randomized in the experimental group were informed of the allocation result and inquired whether they would like to follow the treatment. Five trials used the McNulty-Zelen design, which could be applied in cluster randomized controlled trials and overcome the potential bias of the Hawthorne effect, e.g., trials involving educational interventions. Informed consent was obtained from a third party on behalf of the participants. Intention-to-treat analysis was the main population used in Zelen’s design.
Conclusions: Zelen’s design has a broad application foreground in clinical trials. It also could adapt to research needs by combining with various observational studies. Patient or healthcare consumer involvement: No patients or consumers participated in research activities.