Familywise error control in multi-armed response-adaptive trials
Abstract
Response-adaptive designs allow the randomization probabilities to change during the course of a trial based on cumulated response data, so that a greater proportion of patients can be allocated to the better performing treatments. A major concern over the use of response-adaptive designs in practice, particularly from a regulatory viewpoint, is controlling the type I error rate. In particular, we show that the naive z-test can have an inflated type I error rate even after applying a Bonferroni correction. Simulation studies have often been used to demonstrate error control, but do not provide a guarantee. In this paper, we present adaptive testing procedures for normally distributed outcomes that ensure strong familywise error control, by iteratively applying the conditional invariance principle. Our approach can be used for fully sequential and block randomized trials, and for a large class of adaptive randomization rules found in the literature. We show there is a high price to pay in terms of power to guarantee familywise error control for randomization schemes with extreme allocation probabilities. However, for proposed Bayesian adaptive randomization schemes in the literature, our adaptive tests maintain or increase the power of the trial compared to the z-test. We illustrate our method using a three-armed trial in primary hypercholesterolemia.
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
Read the paper
Related studies
- Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis
- Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials
- Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials
- Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: A systematic review, meta‐analysis, and network meta‐analysis of randomized trials with 94,283 participants
- Screen time increases overweight and obesity risk among adolescents: a systematic review and dose-response meta-analysis
- Exposure to WHO AWaRe antibiotics and isolation of multi-drug resistant bacteria: a systematic review and meta-analysis
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.