Clinical trials : journal of the Society for Clinical Trials
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The rolling six design (RSD) is currently being used by the Children's Oncology Group (COG) as their standard design for Phase I trials. Because the COG has large multi-center trials with fast accrual, the motivation for adopting the RSD is to hasten accrual and shorten the duration of their trials. However, trial suspension due to completion of follow-up still cannot be entirely avoided by the RSD. Therefore, a design that allows continuous enrollment of patients throughout the entire trial is needed. ⋯ The TITE-CRM, which allows for continual enrollment of patients, provides a safe design for pediatric oncology Phase I trials with better accuracy than the RSD.
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Suppose a standard therapy (Standard) has been established to provide a clinically important reduction in risk of irreversible morbidity or mortality. In that setting, the safety and efficacy of an experimental intervention likely would be assessed in a clinical trial providing a comparison with Standard rather than a placebo arm. Such a trial often is designed to assess whether the efficacy of the experimental intervention is not unacceptably worse than that of Standard, and is called a non-inferiority trial. Formally, the non-inferiority trial usually is designed to rule out a non-inferiority margin, defined as the minimum threshold for what would constitute an unacceptable loss of efficacy. ⋯ Non-inferiority trials with non-rigorous margins allow substantial risk for accepting inadequately effective experimental regimens, leading to the risk of erosion in quality of health care. The design and conduct of non-inferiority trials, including selection of non-inferiority margins, should account for many factors that can induce bias in the estimated effect of Standard in the non-inferiority trial and thus lead to bias in the estimated effect of the experimental treatment, for the need to ensure the experimental treatment preserves a clinically acceptable fraction of Standard's effect, and for the particular vulnerability of the integrity of a non-inferiority trial to the irregularities in trial conduct. Due to the inherent uncertainties in non-inferiority trials, alternative designs should be pursued whenever possible.
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Toxicity grades underlie the definition of a dose-limiting toxicity but in the majority of phase I designs, the information contained in the individual grades is not used. Some authors have argued that it may be more appropriate to consider a polytomous rather than dichotomous response. ⋯ Although the gains in performance were not as great as we had hoped, we observed no cases where the performance of continual reassessment method was poorer. Our recommendation is that investigators might consider using graded toxicities at the design stage.
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Whether a pivotal randomized trial will be interpreted in a similar and consistent manner by different regulatory agencies is uncertain as policy perspectives may play a role in data interpretation and the translation of trial results into clinical practice. ⋯ Labeling indications can vary widely in different regulatory environments even when based on the same trial data.
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There is a little empirical evidence to determine which, if any, monitoring practices best achieve the goals of trial monitoring set forth in ICH E6 under the variable circumstances of different clinical trial settings. ⋯ These findings underscore the necessity of research to provide an evidence base for monitoring practice.