Challenges to demonstrating disease-modifying effects in Alzheimer's disease clinical trials.
Challenges to demonstrating disease-modifying effects in Alzheimer's disease clinical trials.
复制标题
DOI：
10.1016/j.jalz.2006.07.001
复制
发表时间：
2006-10-01
期刊：
影响因子：
--
通讯作者：
Cummings, Jeffrey L
中科院分区：
文献类型：
--
作者：
Cummings, Jeffrey L
在了解阿尔茨海默病（AD）的分子生物学方面的进展为疾病修饰干预提供了许多合理的治疗靶点。为了推动这些药物最终获得美国食品药品监督管理局（FDA）的批准，并被医生纳入临床实践，并被患者和护理人员接受，有必要就疾病修饰的含义以及需要哪些信息来提供令人信服的事实基础以区分疾病修饰和对症治疗效果达成共识。疾病改变要求干预对AD的基础病理学和病理生理学产生影响;病程改变、疾病改变或残疾保留是可应用于不影响AD基础神经生物学的对症药物的替代术语。已经提出了各种试验设计，以提供支持疾病调整的信息，包括较基线变化设计、生存类型设计、交错开始设计和交错退出设计。每一种方法都有缺点，试验设计本身不太可能提供足够的信息来最终证明疾病发生了改变。将生物标志物纳入临床试验将支持疾病改变的主张。理想情况下，这种替代标志物应响应于干预，预测对干预的临床响应，并且与受干预影响的途径中的AD的神经生物学强制相关。支持疾病改善的第三个信息轴来源于对AD动物模型中治疗效果的观察。与疾病改善一致的临床结果、来自纳入临床试验的替代标志物的支持以及表明治疗对AD模型的作用的基础科学信息的三联体将联合收割机结合起来，为疾病改善提供令人信服的理由。
Progress in understanding the molecular biology of Alzheimer's disease (AD) has provided a number of plausible therapeutic targets for disease-modifying interventions. To advance these agents toward eventual US Food and Drug Administration (FDA) approval and incorporation into clinical practice by physicians and acceptance by patients and caregivers it is necessary to reach consensus on the meaning of disease modification and on what information is needed to provide a compelling factual basis for distinguishing disease modification from symptomatic treatment effects. Disease modification requires that the intervention have an impact of underlying pathology and pathophysiology of AD; disease course modification, illness modification or disability sparing are alternate terminologies that could be applied to symptomatic agents that do not affect the underlying neurobiology of AD. A variety of trial designs have been proposed to provide information supporting disease modification including change from baseline designs, survival type designs, staggered start designs, and staggered withdrawal designs. Each of these has shortcomings, and by themselves trial designs are not likely to provide sufficient information to conclusively prove that disease modification has occurred. Incorporation of a biomarker into clinical trials will support the claim for disease modification. Such a surrogate marker ideally should respond to the intervention, predict the clinical response to the intervention, and be compellingly related to the neurobiology of AD in the pathway affected by the intervention. A third axis of information supportive of disease modification is derived from observation of the effect of treatment in animal models of AD. The triad of a clinical outcome consistent with disease modification, support from a surrogate marker incorporated into the clinical trial, and basic science information indicating the effect of the therapy on a model of AD would combine to make a convincing case for disease modification.