Abstract
The main development of the thesis was devoted to the problem of dose choice optimization in dose-finding trials, in phase II. We have considered this problem from the perspective of utility functions. We have allocated a utility value to the doses itself, knowing that the sponsor’s problem was now to find the best dose, that is to say, the one having the highest utility. We have limited ourselves to a single utility function, integrating two components: an efficacy-related component (the PoS = the power of a phase III trial - with 1000 patients - of this dose versus placebo) and a safety-related component. For the latter, we chose to characterize it by the predictive probability of observing a toxicity rate lower or equal to a given threshold (that we set to 0.15) in phase III (still for a trial of 1000 patients in total). This approach has the advantage of being similar to the concepts used in phase I trials in Oncology, which particularly aim to find the dose related to a limiting toxicity (notion of "Dose limiting Toxicity").We have adopted a Bayesian approach for the analysis of phase II data. Apart from the known theoretical advantages of the Bayesian approach compared with the frequentist approach (respect of the likelihood principle, less dependency on asymptotic results, robustness), we chose this approach for several reasons:• It provides a more flexible framework for the decision-making of the sponsor because it offers the possibility to combine (by definition of the Bayesian approach) a priori information with the available data: in particular, it offers the possibility to integrate, more or less explicitly, the information available outside the phase II trial.• The Bayesian approach allows greater flexibility in the formalization of the decision rules.We studied the properties of decision rules by simulating phase II trials of different sizes: 250, 500 and 1000 patients. For the last two designs (500 and 1000 patients in phase II), we have also evaluated the interest of performing an interim analysis when half of the patients are enrolled (i.e. with the first 250and the first 500 patients included respectively). The purpose was then to evaluate whether or not, for larger phase II trials, allowing the possibility of choosing the dose in the middle of the study and continuing the study to the end if the interim analysis is not conclusive, could reduce the size of the phase II trial while preserving the relevance of the final dose choice.