Alzheimer's disease drug development: old problems require new priorities.
Alzheimer's disease drug development: old problems require new priorities.
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DOI：
10.2174/187152708787122950
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Greig NH
中科院分区：
文献类型：
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作者：
Becker RE;Greig NH
阿尔茨海默氏病（AD）临床药物开发和患者护理依赖于评级工具、研究设计和方法以及临床试验（CT）结果到临床的转化，而没有能够控制以下的标准化方案的支持：（i）观察中的随机测量误差侵入，（ii）临床评估者引入的不准确性和偏差，（iii）研究地点与研究方案条件的一致性，（iv）CT为从业者模拟个体患者最有效使用药物的能力，以及（v）能够使研究和患者护理数据无效的其他因素。这种对AD方法的放松态度现在可能正在改变，阿尔茨海默病神经影像学倡议（ADNI）的证据表明，需要仔细标准化的协议来验证用于AD诊断，药物开发和患者护理的生物标志物。在精神病学和AD领域，最近的研究已经发现了严重的不准确性，不精确性，偏见和妥协的研究协议能够无效CT结果数据和结论从这些数据。这一有限但令人不安的证据加强了ADNI对更详细的方法协议的呼吁。基于CT和患者护理中与评定结果相关的精确度和准确度的限制，我们呼吁优先考虑生物标志物作为AD药物开发和患者护理中的结果变量的资格和使用，并确保生物标志物的有效使用，以开发ADNI研究中建模的方案指导实践。为了满足临床药理学的治疗目的，我们得出结论，AD CT需要为临床医生设置显示有效的药物的使用条件，生物标志物替代终点作为药物靶点，而不仅仅是在当前临床实践确定的现场条件下进行的疗效试验。
Alzheimer’s disease (AD) clinical drug development and patient care depend on rating instruments, research designs and methods, and translations of clinical trial (CT) results into the clinic without support from standardized protocols able to control (i) random measurement error intrusions into observations, (ii) inaccuracy and bias introduced by clinical evaluators, (iii) conformity of research sites to conditions of research protocols, (iv) the ability of the CT to model for practitioners the most effective use of the drug with individual patients, and (v) other factors able to invalidate research and patient care data. This relaxed attitude with regard to AD methods may be changing now with Alzheimer’s Disease Neuroimaging Initiative (ADNI) evidence that carefully standardized protocols are needed to validate biomarkers for use in AD diagnosis, drug development, and patient care. In the fields of psychiatry and AD, recent studies have detected serious inaccuracies, imprecision, biases and compromises of study protocols able to invalidate CT outcome data and conclusions drawn from these data. This limited but troubling evidence reinforces ADNI calls for more detailed methodological protocols. Based on the limits to precision and accuracy associated with rated outcomes in CTs and patient care, we call for priority to be given to the qualification and use of biomarkers as outcome variables in AD drug development and patient care and, to insure effective uses of biomarkers, to development of protocol guided practices being modeled in ADNI research. To meet clinical pharmacology’s therapeutic aims we conclude that AD CTs need to set for clinicians the conditions of use of drugs shown efficacious, biomarker surrogate endpoints as drug targets, and not to function merely as tests for efficacy conducted under field conditions determined by current clinical practices.