Experimental designs for drug combination studies

The interest in drug combinations is growing rapidly due to the opportunities they create to increase the therapeutic effect and to reduce the frequency or magnitude of undesirable side effects when single drugs fail to deliver satisfactory results. Considerable effort in studying the mechanisms leading to the benefits of the joint action of drugs has been matched by the development of relevant statistical methods and tools for statistical analysis of the data obtained in such studies that allow important statistical assumptions to be taken into account, i.e. the appropriate statistical model and the distribution of the response of interest (e.g. Gaussian, Binomial, Poisson). However, much less attention has been given to the choice of suitable experimental designs for such studies, while only high quality data can ensure that the objectives of the studies will be fulfilled. We propose methods for construction of such experimental designs which are economical and make most efficient use of the available resources. We also propose simple but flexible experimental designs, which we call ray-contour designs, which are particularly useful when the use of low or high doses is undesirable and hence a standard statistical analysis of the data is not possible.