Randomized Method for Dose Response Study Permuted Block by Block Randomization

Randomization is necessary for reducing bias in clinical studies, especially confirmatory studies. Since the 1970s, researchers proposed various methods of randomization. This has resulted in randomization becoming one of the most effective methods for bias control in clinical studies. Zelen proposed the importance of randomization and applied the permuted block randomization to a clinical study. After his work, Efron proposed the biased coin design in order to balance treatment assignments. Using Efron’s biased coin design; the probability of assignment to the other group is constant, regardless of the degree of imbalance. Wei developed an adaptive biased coin design where the probabilities of assignment adapt according to the degree of imbalance. Despite the value of these randomization methods, the permuted block randomization is the preferred method used in clinical studies. This permuted block method is simple and easily controls the randomization of equal numbers of patients into each treatment group at each center. But the permuted randomization method has some shortcomings, one of which is predicting the allocation as it nears the end of block. This predictability of allocation induces some biases, especially selection bias. Increasing the block size leads to a lower predictability. However, increasing the block size is difficult in studies which includes several treatment groups because a large number of patients have to be randomized at each center. This causes incomplete randomization in several of the centers. Therefore, we propose the following method for improving permuted block randomization.