Optimal Design of Multicentre Clinical Trials with Random Enrolment
Optimal Design of Multicentre Clinical Trials with Random Enrolment
Vladimir Anisimov, Valerii Fedorov and Byron Jones
ABSTRACT. Fedorov et al. (2002) gave formulae for the variance of the estimated ECRT (expected combined response to treatment) and the optimal number of centres and total number of patients to use in a multicentre trial in a setting where the number of patients on each treatment arm in each centre was considered fixed. Here we extend these results to the setting where enrolment at each centre is considered random. We show that such randomness inflates the size of the variance of the estimated ECRT and give formulae for amount of inflation. We also show that this inflation factor is increased if the enrolment rates vary over the centres.
The time to complete enrolment is a crucial component in the problem of optimal study design. We consider the time to complete enrolment under three different policies: competitive, balanced and restricted. For the first two of these we give explicit formulae that may be used to calculate the probability density function of the time to complete enrolment. For restricted enrolment we illustrate how the distribution of the time to complete enrolment may be calculated using simulation.
Finally for “pairwise” competitive enrolment we give formulae for the optimal number of centres and total number of patients for the case in which a risk function takes into account randomness in enrolment. For more realistic enrolment scenarios we can apply numerical optimization based on simulation.
