An optimised multi-arm multi-stage clinical trial design for unknown variance.


Change log
Authors
Grayling, Michael J 
Wason, James MS 
Mander, Adrian P 
Abstract

Multi-arm multi-stage trial designs can bring notable gains in efficiency to the drug development process. However, for normally distributed endpoints, the determination of a design typically depends on the assumption that the patient variance in response is known. In practice, this will not usually be the case. To allow for unknown variance, previous research explored the performance of t-test statistics, coupled with a quantile substitution procedure for modifying the stopping boundaries, at controlling the familywise error-rate to the nominal level. Here, we discuss an alternative method based on Monte Carlo simulation that allows the group size and stopping boundaries of a multi-arm multi-stage t-test to be optimised, according to some nominated optimality criteria. We consider several examples, provide R code for general implementation, and show that our designs confer a familywise error-rate and power close to the desired level. Consequently, this methodology will provide utility in future multi-arm multi-stage trials.

Description
Keywords
Familywise error-rate, Group sequential, Interim analyses, Multi-arm multi-stage, t-Statistic, Analysis of Variance, Clinical Trials as Topic, Data Interpretation, Statistical, Endpoint Determination, Humans, Monte Carlo Method, Research Design, Sample Size
Journal Title
Contemp Clin Trials
Conference Name
Journal ISSN
1551-7144
1559-2030
Volume Title
67
Publisher
Elsevier BV
Sponsorship
MRC (unknown)
MRC (unknown)