Methodology of Phase I and II trials of anticancer CAM

背景：抗癌CAM疗法正日益成为科学研究的焦点。早期试验的传统方法可能不适用于某些CAM方法的开发。也许正因为如此，许多用于癌症临床试验的辅助替代疗法以前没有进行过剂量测定；此外，CAM的二期试验常常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。这些方法可以有效地适用于CAM的研究。

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.