A re-randomisation design for clinical trials.

Brennan C Kahan,Caroline J Doré,Tim P Morris,Andrew B Forbes

doi:10.1186/s12874-015-0082-2

Abstract

BackgroundRecruitment to clinical trials is often problematic, with many trials failing to recruit to their target sample size. As a result, patient care may be based on suboptimal evidence from underpowered trials or non-randomised studies.MethodsFor many conditions patients will require treatment on several occasions, for example, to treat symptoms of an underlying chronic condition (such as migraines, where treatment is required each time a new episode occurs), or until they achieve treatment success (such as fertility, where patients undergo treatment on multiple occasions until they become pregnant). We describe a re-randomisation design for these scenarios, which allows each patient to be independently randomised on multiple occasions. We discuss the circumstances in which this design can be used.ResultsThe re-randomisation design will give asymptotically unbiased estimates of treatment effect and correct type I error rates under the following conditions: (a) patients are only re-randomised after the follow-up period from their previous randomisation is complete; (b) randomisations for the same patient are performed independently; and (c) the treatment effect is constant across all randomisations. Provided the analysis accounts for correlation between observations from the same patient, this design will typically have higher power than a parallel group trial with an equivalent number of observations.ConclusionsIf used appropriately, the re-randomisation design can increase the recruitment rate for clinical trials while still providing an unbiased estimate of treatment effect and correct type I error rates. In many situations, it can increase the power compared to a parallel group design with an equivalent number of observations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-015-0082-2) contains supplementary material, which is available to authorized users.

Highlights

Recruitment to clinical trials is often problematic, with many trials failing to recruit to their target sample size
Under certain conditions, the re-randomisation design can provide unbiased estimates of treatment effect, correct type I error rates, and similar, or even increased power compared to that of a parallel group trial of the same size
Properties of the re-randomisation design We demonstrate that the rerandomisation design will provide asymptotically unbiased estimates of treatment effect and correct type I error rates under the following conditions: (a) Patients are only eligible for re-randomisation when the follow-up period from their previous randomisation is complete; (b)Randomisations for the same patient are performed independently for each randomisation period; (c) The treatment effect is constant across all randomisation periods

Summary

Introduction

Recruitment to clinical trials is often problematic, with many trials failing to recruit to their target sample size. Patient recruitment is often a major challenge for randomised controlled trials (RCTs), and has been identified as the number one research priority by leads of UK trials units [1]. Reviews of publicly funded UK trials have found that between 45-69 % fail to successfully recruit to target [2, 3]. Failure to recruit patients in a timely manner can have a major impact on patient care. It can lead to delays in completing trials, which in turn can cause delays in successful new treatments being adopted into routine clinical. Patients with an underlying condition for which symptoms recur will require treatment for each new presentation of symptoms (e.g. patients with sickle cell disease require pain relief each time they have a sickle cell pain crisis). For some conditions an intervention may be given on a repeated basis until the patient is considered to be a treatment success

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