Model calibration in the continual reassessment method

BACKGROUND: The continual reassessment method (CRM) is an adaptive model-based design used to estimate the maximum tolerated dose in dose finding clinical trials. A way to evaluate the sensitivity of a given CRM model including the functional form of the dose-toxicity curve, the prior distribution on the model parameter, and the initial guesses of toxicity probability at each dose is using indifference intervals. While the indifference interval technique provides a succinct summary of model sensitivity, there are infinitely many possible ways to specify the initial guesses of toxicity probability. In practice, these are generally specified by trial and error through extensive simulations. METHODS: By using indifference intervals, the initial guesses used in the CRM can be selected by specifying a range of acceptable toxicity probabilities in addition to the target probability of toxicity. An algorithm is proposed for obtaining the indifference interval that maximizes the average percentage of correct selection across a set of scenarios of true probabilities of toxicity and providing a systematic approach for selecting initial guesses in a much less time-consuming manner than the trial-and-error method. The methods are compared in the context of two real CRM trials. RESULTS: For both trials, the initial guesses selected by the proposed algorithm had similar operating characteristics as measured by percentage of correct selection, average absolute difference between the true probability of the dose selected and the target probability of toxicity, percentage treated at each dose and overall percentage of toxicity compared to the initial guesses used during the conduct of the trials which were obtained by trial and error through a time-consuming calibration process. The average percentage of correct selection for the scenarios considered were 61.5 and 62.0% in the lymphoma trial, and 62.9 and 64.0% in the stroke trial for the trial-and-error method versus the proposed approach. LIMITATIONS: We only present detailed results for the empiric dose toxicity curve, although the proposed methods are applicable for other dose-toxicity models such as the logistic. CONCLUSIONS: The proposed method provides a fast and systematic approach for selecting initial guesses of probabilities of toxicity used in the CRM that are competitive to those obtained by trial and error through a time-consuming process, thus, simplifying the model calibration process for the CRM.