Methodology of Phase I and II trials of anticancer CAM

描述（由申请人提供）：背景：抗癌CAM疗法正日益成为科学研究的焦点。早期试验的常规方法可能不适用于某些CAM方法的开发。也许正因为如此，许多CAM治疗癌症的临床试验以前没有受到剂量发现;此外，CAM的II期试验往往未能纳入正式的统计设计。近年来，为了应对研究免疫、生物和靶向药物的挑战，已经开发了I期和II期试验的新设计。这些方法可能是有益的适应CAM的研究。 目的：系统地回顾CAM治疗癌症的早期试验中应用的方法;系统地回顾此类试验的可用方法;根据模拟和分析研究为未来CAM试验提出具体实用的建议。 方法：将对CAM在癌症中的I期、II期和III期试验进行三项独立的系统评价。这些将描述先前的研究并确定以下部分的比例：试图找到最佳剂量的I期试验;在剂量探索试验之前进行的II期和III期试验;纳入正式统计设计的I期试验;在II期试验之前进行的III期试验。将对I期和II期设计进行系统评价：将通过预先规定的标准描述每种设计。将通过模拟和分析研究来评估CAM的关键第一阶段和第二阶段设计的操作特性。将为四种“原型”CAM模式生成四组剂量-反应和剂量-毒性函数。将针对每种模式对每种I期设计进行检测：将计算研究剂量与理论推导的最佳剂量的效率和接近程度。 II期设计将在CAM治疗常见的一系列临床场景下进行测试：将比较设计之间的样本量和研究持续时间。这些研究的结果将以非技术术语表示，以便CAM研究人员可以根据对研究模式和癌症人群特性的简单假设来选择I期和II期设计。

DESCRIPTION (provided by applicant): BACKGROUND: Anticancer CAM therapies are increasingly becoming the focus of scientific research. Conventional approaches to early phase trials may not be applicable for the development of some CAM approaches. Perhaps as a result, many CAM therapies taken to clinical trial in cancer have not previously been subject to dose-finding; furthermore, Phase II trials of CAM have often failed to incorporate formal statistical designs. In recent years new designs for Phase I and II trials have been developed in response to the challenges of researching immune, biologic and target-based agents. These methodologies might be usefully adapted for the study of CAM. OBJECTIVES: To review systematically methodologies that have been applied in early phase trials of CAM for cancer; to review systematically available methodologies for such trials; to make specific practical recommendations for future CAM trials based on simulation and analytic studies. METHODS: Three separate systematic reviews will be undertaken of Phase I, II and III trials of CAM in cancer. These will describe previous research and determine the proportion of: Phase I trials that attempted to find an optimal dose; Phase II and III trials that were preceded by dose finding trials; Phase I trials that incorporated a formal statistical design; Phase Ill trials that were preceded by Phase II.A systematic review will be undertaken of Phase I and II designs: each design will be described by pre-specified criteria. The operating characteristics of key Phase I and II designs for CAM will be assessed by simulation and analytic studies. Four sets of dose-response and dose-toxicity functions will be generated for four "archetypal" CAM modalities. Each Phase I design will be tested for each modality: efficiency and closeness of the study dose to a theoretically derived optimal dose will be calculated. Phase II designs will be tested given a range of clinical scenarios common for CAM therapies: sample size and study duration will be compared between designs. The results of these studies will be expressed in non-technical terms so that CAM researchers can make a choice of Phase I and II design depending on simple assumptions about the properties of the modality and cancer population under study.