Testing multiple dose combinations in clinical trials

Drug combination trials are often motivated by the fact that individual drugs target the same disease but via different routes. A combination of such drugs may then have an overall better effect than the individual treatments which has to be verified by clinical trials. Several statistical methods have been explored that discuss the problem of comparing a fixed-dose combination therapy to each of its components. But an extension of these approaches to multiple dose combinations can be difficult and is not yet fully investigated. In this paper, we propose two approaches by which one can provide confirmatory assurance with familywise error rate control, that the combination of two drugs at differing doses is more effective than either component doses alone. These approaches involve multiple comparisons in multilevel factorial designs where the type 1 error can be controlled first, by bootstrapping tests, and second, by considering the least favorable null configurations for a family of union intersection tests. The main advantage of the new approaches is that their implementation is simple. The implementation of these new approaches is illustrated with a real data example from a blood pressure reduction trial. Extensive simulations are also conducted to evaluate the new approaches and benchmark them with existing ones. We also present an illustration of the relationship between the different approaches. We observed that the bootstrap provided some power advantages over the other approaches with the disadvantage that there may be some error rate inflation for small sample sizes.