Effects of unstratified and centre-stratified randomization in multi-centre clinical trials

What is it about?

This paper deals with the analysis of randomization effects in multi-centre clinical trials. The two randomization schemes most often used in clinical trials are considered: unstratified and centre-stratified block-permuted randomization. The prediction of the number of patients randomized to different treatment arms in different regions during the recruitment period accounting for the stochastic nature of the recruitment and effects of multiple centres is investigated. A new analytic approach using a Poisson-gamma patient recruitment model (patients arrive at different centres according to Poisson processes with rates sampled from a gamma distributed population) and its further extensions is proposed. Closed-form expressions for corresponding distributions of the predicted number of the patients randomized in different regions are derived. In the case of two treatments, the properties of the total imbalance in the number of patients on treatment arms caused by using centre-stratified randomization are investigated and for a large number of centres a normal approximation of imbalance is proved. The impact of imbalance on the power of the study is considered. It is shown that the loss of statistical power is practically negligible and can be compensated by a minor increase in sample size. The influence of patient dropout is also investigated. The impact of randomization on predicted drug supply overage is discussed.

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Why is it important?

Randomization is an essential part of clinical trial design. It is carried out with the purpose of allocating patients to treatments randomly, preserving the blind and achieving balance in the number of patients on treatment arms. The choice of randomization affects the power of statistical tests and the amount of drug supply required to satisfy patient demand. The results of the paper provide the opportunity to investigate the impact of patient recruitment together with the randomization scheme on the power and sample size of a multi-centre study.

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