Clinical trials : journal of the Society for Clinical Trials
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Benjamin Freedman has argued in 1987 that before a controlled trial is started, there should be 'genuine uncertainty in the expert medical community about the preferred treatment'. Freedman's definition of the concept is widespread in clinical research, but has been controversial since its start. Over the past decade, the equipoise controversy has become increasingly complex. ⋯ There is no decisive reason to give up on the equipoise requirement.
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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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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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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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There is a debate among cancer researchers about the use of single-arm or randomized phase II clinical trial designs; however, there is limited published objective evaluation of this issue. ⋯ Both single-arm and randomized phase II trials appear warranted in certain situations. Investigators should increase consideration of the potential impact on phase III trials to optimally select the proper trial design prior to phase II study implementation.