This JAMA Guide to Statistics and Methods reviews the use of prerandomization run-in periods to improve treatment adherence and reduce loss to follow-up, and explains how they should be interpreted.
A prerandomization run-in is a period between screening a potential trial participant and their being randomized. In a 2019 article in JAMA Network Open, Fukuoka et al1 evaluated whether a mobile phone education application and in-person counseling could increase physical activity in 210 study participants. A prerandomization run-in was used to improve adherence and determine baseline physical activity levels of the participants. In this chapter, the advantages and limitations of run-in periods are reviewed.
Description of the Method
A potential participant is screened and asked for consent to take part in the trial but is not immediately randomized. Instead, for a period of weeks or months, the participant may try the intervention (or placebo) to determine if they are likely to be adherent to the study protocol if they were to be randomized. Participants are typically assessed at least twice before randomization to allow consent to be reconfirmed, adherence to treatment or with data collection determined, and baseline and end of run-in measures obtained. Only at the later assessment would the participant be randomized if they had been adherent with the study protocol and met all the inclusion criteria.
Why Are Run-in Periods Used in Trials?
For trialists, a key aim of the prerandomization run-in period is to improve adherence to trial treatments or procedures and to reduce loss to follow-up with consequent improvement in statistical power. A run-in also may allow assessment of treatment tolerability, response to treatment, or both. From the perspective of trial participants, a run-in allows time to reflect on whether they remain willing to be randomized, including giving more time to understand trial information, experience study procedures, and discuss participation with their managing physicians or family before committing to a long-term trial.
Nonadherence in clinical trials leads to systematic underestimation of the expected treatment effect that would result from actually taking the treatment (ie, 100% adherence and no drop-ins in the control group).2 A basic principle of randomized trials is that each participant is analyzed in the group to which they were assigned, irrespective of their adherence (ie, an intention-to-treat analysis).3 Undertaking “per-protocol” analyses (ie, analyzing only those who were adherent) introduces bias because of inherent differences between those who do or do not adhere to the trial protocol. By excluding participants likely to be poorly adherent or being unwilling to collect adequate data (such as occurred in the study by Fukuoka et al) before randomization, a run-in period can reduce the risk of bias due to differential dropout or data collection and improve statistical power.