Randomization in clinical studies

Abstract

Randomized controlled trial is widely accepted as the best design for evaluating the efficacy of a new treatment because of the advantages of randomization (random allocation). Randomization eliminates accidental bias, including selection bias, and provides a base for allowing the use of probability theory. Despite its importance, randomization has not been properly understood. This article introduces the different randomization methods with examples: simple randomization; block randomization; adaptive randomization, including minimization; and response-adaptive randomization. Ethics related to randomization are also discussed. The study is helpful in understanding the basic concepts of randomization and how to use R software.

Keywords: Adaptive randomization; Minimization; Random allocation; Randomization; Randomized controlled trial; Restrictive randomization; Simple randomization.

Fig. 1.

Influence of sample size ratio in two groups on power (difference (d) = 0.9, two-tailed, significant level = 0.05). The dashed line indicates the same sample size in two groups (n = 20) and maximized power.

Fig. 2.

Probability curves of imbalance between two groups for complete randomization as a function of total sample size (n). When n = 40, there is a 52.7% chance of imbalance beyond 10% (allocation ratio 45%–55%) (point A). When n = 200, there is a 15.7% chance of imbalance (point B), but n = 400 results in only 4.6% chance of imbalance (point C).

Fig. 3.

Example of stratification with three prognostic factors (site, sex, and age band). Eventually, randomization with 12 strata should be accomplished using 12 separate randomization processes. C: control group, T: treatment group.