Regulatory Guidance on Randomization and the Use of Randomization Tests in Clinical Trials: A Systematic Review

Abstract

Randomization is a critical aspect of the clinical trial. Regulatory guidance plays a role in clinical research. Randomization tests provide valid methodology for statistical inference. In the present paper, we intended to survey: (a) information contained in regulatory guidance on randomization; and (b) the use of randomization tests in trials supporting marketing applications. This systematic review used the Cortellis Regulatory Intelligence database (IDRAC). For (a), of n = 156 guidance documents, nine provided recommendations on randomization methods. For (b), n = 48 trials (52 submissions) employed randomization tests. 40 (83.3%) were phase III trials, 31 (64.6%) employed dynamic allocation. Randomization test was the primary in 5 (10.4%), and sensitivity analysis in 34 (70.8%) trials. Furthermore, randomization tests were performed when treatment allocation was not according to plan (4 (8.3%)), or violations of model assumptions (5 (10.4%)) were observed. Overall, there are sparse recommendations on randomization in current regulatory guidance, with little mention of recently developed methods which might outperform current practice in certain contexts. Greater adoption of such methods in pharmaceutical industry trials may lead to a better shared sense between regulators and trial sponsors on their appropriate use. Randomization tests are employed with greater frequency, reflecting increased appreciation of the validity and value of randomization tests.