Unequal allocation in randomised phase II trials

Abstract

Background

Equal allocation is accepted almost universally in the design of randomised clinical trials and it is often assumed that this approach provides the most efficient use of available resources. The design of a phase II study often depend on a binary endpoint with assessments of efficacy made using an odds ratio. In a trial setting however, precision about this odds ratio will only be optimal under equal allocation when there is no difference in the response rates between two treatment arms. A result which typically is of limited clinical interest.

Methodology

For a clinical trial with response rates are p_x and p_y in the experimental and control arm respectively, allocation proportions are derived that seek to maximise the precision about an odds ratio in settings where difference between response rates are expected. Sample size calculations are performed and compared to study designs using equal allocation.

Results

Sample size calculations based on the exact methods of Jung and Sargent [8] show that under the same type 1 error rate and power, the required sample sizes using unequal allocation ratios are smaller than those where equal allocation is used. This discrepancy is greater as the control mean response rate tends towards 0 or 1 while the relative treatment effect remain fixed.

Discussion

Trialist involved in the design of phase II studies should take account of possible savings in sample size that may be gained by unequal allocation of patients.