Randomization Strategies

Randomized controlled trials (RCTs) are the gold standard research design to determine the clinical efficacy or clinical effectiveness of medical interventions. One of the key methodological features is the random allocation of study participants to the study groups of interest. Random allocation means that treatment assignment is purely due to chance. Successful randomization maximizes the validity of study findings by reducing or eliminating sources of bias that may mask the true treatment effect. Common randomization methods include simple randomization, block randomization, stratified randomization, and adaptive randomization. The most common method of simple randomization is a fair coin toss, which has an equal chance of landing on either “heads” or “tails.” In a study comparing two groups, flipping a fair coin gives each study participant a 50% chance of being assigned to one of the two groups. Simple randomization methods are prone to producing groups that are unbalanced with respect to size and covariates. Blocked randomization, stratified randomization, and adaptive randomization methods were developed to mitigate this imbalance. In a block randomization schema, participants are first assigned to a block and subsequently randomly assigned to a treatment group within the assigned block. These methods help to balance the number of study patients in each group. Similar to block randomization, the first step of a stratified randomization method is to assign participants to a stratum which is defined by a covariate or confounder. After assignment to a stratum, study participants are then randomly allocated to a treatment within the stratum. Adaptive randomization methods dynamically adjust the allocation probabilities as each patient is enrolled. Such methods allow the research team to monitor allocation balance in real time. There are also ethical and logistical issues to consider with randomization. One of the primary ethical considerations is equipoise. Study equipoise is determined by the inclusion/exclusion criteria and the treatment assignments. When a clinical investigators’ personal clinical equipoise is not aligned with the study equipoise, their decisions of which patients to enroll may be biased. Maintaining and aligning study and clinical equipoise is vital to the validity of the study findings. The logistical feasibility of randomization methods can be determined by conducting a pilot study which serves as a trial run of the full trial. During a pilot study, the research team can ensure that the investigators have equipoise and patients are willing to accept their random assignment. Additionally, the team can test all software used for randomization, create communication plans with the care team, and ensure that everyone is properly trained on all study procedures. Pilot studies provide the research team an opportunity to make any adjustments needed to improve all study processes before the full trial is launched.