Zelen design clinical trials: why, when, and how

Abstract

Background In 1979, Marvin Zelen proposed a new design for randomized clinical trials intended to facilitate clinicians’ and patients’ participation. The defining innovation of Zelen’s proposal was random assignment of treatment prior to patient or participant consent. Following randomization, a participant would receive information and asked to consent to the assigned treatment. Methods This narrative review examined recent examples of Zelen design trials evaluating clinical and public health interventions. Results Zelen designs have often been applied to questions regarding real-world treatment or intervention effects under conditions of incomplete adherence. Examples include evaluating outreach or engagement interventions (especially for stigmatized conditions), evaluating treatments for which benefit may vary according to participant motivation, and situations when assignment to a control or usual care condition might prompt a disappointment effect. Specific practical considerations determine whether a Zelen design is scientifically appropriate or practicable. Zelen design trials usually depend on identifying participants automatically from existing records rather than by advertising, referral, or active recruitment. Assessments of baseline or prognostic characteristics usually depend on available records data rather than research-specific assessments. Because investigators must consider how exposure to treatments or interventions might bias ascertainment of outcomes, assessment of outcomes from routinely created records is often necessary. A Zelen design requires a waiver of the usual requirement for informed consent prior to random assignment of treatment. The Revised Common Rule includes specific criteria for such a waiver, and those criteria are most often met for evaluation of a low-risk and potentially beneficial intervention added to usual care. Investigators and Institutional Review Boards must also consider whether the scientific or public health benefit of a Zelen design trial outweighs the autonomy interests of potential participants. Analysis of Zelen trials compares outcomes according to original assignment, regardless of any refusal to accept or participate in the assigned treatment. Conclusions A Zelen design trial assesses the real-world consequences of a specific strategy to prompt or promote uptake of a specific treatment. While such trials are poorly suited to address explanatory or efficacy questions, they are often preferred for addressing pragmatic or policy questions.

A first step towards best practice recommendations for the design and statistical analyses of pragmatic clinical trials: A modified Delphi approach

“…Minimize the risk of switching if this would be a problem for data analyses: Inform physicians participants that for the period of the trial treatment switching should be avoided. In case there is a risk of substantial proportion of treatment switching, physicians' preference or subversion, the Zelen design can be considered 54 . This design intends to facilitate clinicians' and patients' participation by randomizing patients prior to participation consent. …”

Randomized controlled trial of an internet-based self-guided hand exercise program to improve hand function in people with systemic sclerosis: the Scleroderma Patient-centered Intervention Network Hand Exercise Program (SPIN-HAND) trial

“…The cmRCT design is a post-randomization consent trial design [ 63 – 65 ]. In post-randomization consent trial designs with individual randomization (i.e., not cluster designs), randomization is done based on eligibility criteria prior to obtaining consent from participants.…”

Training community-based psychotherapists to maintain a therapeutic alliance: A psychotherapy practice research network study.

“…Nevertheless, we cannot rule out that significant differential therapist attrition and that control therapists being aware of their control condition status may have biased the findings and may represent an important confound. Perhaps using a Zellen design (Simon et al, 2021) in future research, in which participants are first randomized to condition prior to providing consent, may reduce the differential uptake across conditions. Second, the sample size of therapists was small, especially in the control condition.…”