Bias Control in Randomized Controlled Clinical Trials
In clinical trials, randomization is used to allocate patients to treatment groups, because this design technique tends to produce comparability across treatment groups. However, even randomized clinical trials are still susceptible to bias. Bias is a systematic distortion of the treatment effect estimate. This chapter introduces two types of bias that may occur in clinical trials, selection bias and chronological bias. Selection bias may arise from predictability of the randomization sequence, and different models for predictability are presented. Chronological bias occurs due to unobserved time trends that influence patients’ responses, and its effect on the rejection rate of parametric hypothesis tests for the treatment effect will be revealed. It will be seen that different randomization procedures differ in their susceptibility to bias. A method to reduce bias at the design stage of the trial and robust testing strategies to adjust for bias at the analysis stage are presented to help to mitigate the potential for bias in randomized controlled clinical trials.
KeywordsSelection bias Chronological bias Restricted randomization Type I error Power
- ICH (1998) International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline: statistical principles for clinical trials E9Google Scholar
- Langer S (2014) The modified distribution of the t-test statistic under the influence of selection bias based on random allocation rule. Master’s thesis, RWTH Aachen University, GermanyGoogle Scholar
- Rosenberger W, Lachin J (2015) Randomization in clinical trials: theory and practice. Wiley series in probability and statistics. Wiley, HobokenGoogle Scholar
- Salama I, Ivanova A, Qaqish B (2008) Efficient generation of constrained block allocation sequences. Stat Med 27(9):1421–1428. https://doi.org/10.1002/sim.3014. https://onlinelibrary.wiley.com/doi/abs/10.1002/sim.3014, https://onlinelibrary.wiley.com/doi/pdf/10.1002/sim.3014MathSciNetCrossRefGoogle Scholar