When randomization is not random: Allocation bias in small sample, group sequential randomized clinical trials

Even in rare diseases, where the sample size is limited and blinding is less frequently implemented, randomized controlled trials are considered the gold standard to prove efficacy. Randomization is used to mitigate bias and regulatory guidance recommend the investigation of the impact of bias on the test decision. We quantified how allocation bias affects the test decision in small-sample two-arm group sequential trials under a biasing policy based on the Blackwell-Hodges convergence strategy. Type I error and power were evaluated under Lan-DeMets spending (Pocock-, O'Brien-Fleming-, Wang-Tsiatis-type functions), with and without futility (non-binding, binding), varying interim timing, number of looks and stage-wise restarting of randomization. Allocation bias inflated type I error most for more restrictive randomization procedures, especially permuted blocks with small block sizes. Spending more alpha at interim reduced inflation. Non-binding futility reduced type I error, while binding increased type I error inflation for more aggressive stopping boundaries. Stage-wise restarting modestly reduced inflation for most procedures. Overall, group sequential choices had secondary effect and did not rescue a predictable randomization scheme. When allocation bias cannot be ruled out (e.g. open-label trials), we recommend less restrictive randomization procedures (e.g. big stick design) or, if using permuted blocks, large block sizes.