Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes.
Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes.
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DOI：
10.1111/cts.12491
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Cummings J
中科院分区：
文献类型：
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作者：
Cummings J
阿尔茨海默病（AD）药物开发具有很高的失败率。药物开发决策可以根据从过去试验中吸取的经验教训加以改进。改善动物模型的解释、I期和II期试验中更好的药理学表征、适当的样本量、生物标志物支持的AD诊断、优化全球招募以及避免不适当的亚组分析可以提高药物开发成功率。阿尔茨海默病（AD）在65岁之后每5年频率加倍，并且随着世界人口老龄化而变得越来越常见。据估计，仅在美国，AD患者的数量将从现在的530万激增到2050年的近1400万。为了应对这一迫在眉睫的公共卫生灾难，迫切需要发现和开发新的药物来预防、延迟发病、减缓进展或治疗AD的认知和行为症状。AD药物开发已被证明异常困难，在2002年至2012年的十年中失败率为99.6% 2;目前，成功率仍处于同样低的水平。每项临床试验都为一系列狭窄的问题提供了证据。例如，在特定时间段内给予该剂量的测试试剂是否（例如，18-24个月的疾病缓解治疗[DMT]），以确定的人群（例如，临床前AD;前驱AD;轻度、中度或重度AD痴呆）与安慰剂相比，在预先规定的主要结局（如测量认知的结局）较基线的变化方面产生统计学显著性差异（例如，阿尔茨海默病评估量表-认知部分）3和功能（例如，阿尔茨海默病日常生活活动量表）。4关于对其他人群的影响、其他剂量、其他暴露持续时间以及对其他仪器的影响的问题必须在单独的试验中解决。这些对临床试验的复杂限制已经发展到允许他们以监管机构（如美国食品和药物管理局（FDA）和欧洲药品管理局）可接受的方式定义疗效。监管机构接受这些数据是获得上市批准并使患者广泛使用该药物的唯一途径。
Alzheimer disease (AD) drug development has a high failure rate. Drug development decision making can be improved based on lessons learned from past trials. Improved interpretation of animal models, better pharmacologic characterization in phase I and phase II trials, appropriate sample size, diagnosis of AD with biomarker support, optimization of global recruitment, and avoiding inappropriate subgroup analyses can improve drug development success rates. Alzheimer disease (AD) doubles in frequency every 5 years after the age of 65 years and is becoming increasingly common as the world’s population ages. It is estimated that in the United States alone, the number of patients with AD will burgeon from 5.3 million now to nearly 14 million by 2050. 1 To address this impending public health disaster, there is an urgent need to discover and develop new drugs to prevent, delay the onset, slow the progression, or treat the cognitive and behavioral symptoms of AD. AD drug development has proven to be unusually difficult with a 99.6% failure rate in the decade of 2002 to 20122; currently, the success rate continues at the same low level. Each clinical trial provides evidence on a narrow range of questions. For example, does this dose of the test agent, given for a specific period of time (eg, 18–24 months for disease-modifying therapies [DMTs]), to a defined population (eg, preclinical AD; prodromal AD; mild, moderate, or severe AD dementia) produce a statistically significant difference compared with placebo in change from baseline on the prespecified primary outcomes, such as those measuring cognition (eg, the Alzheimer’s Disease Assessment Scale–Cognitive Portion) 3 and function (eg, the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale). 4 Questions regarding effects in other populations, other doses, other exposure durations, and effects on other instruments must all be addressed in separate trials. These complex constraints on clinical trials have evolved to allow them to define efficacy in a way that is acceptable to regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency. Regulatory acceptance of the data is the only way to gain marketing approval and make the agent widely available to patients.
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影响因子：
120.1
作者：
Cook, David;Brown, Dearg;Pangalos, Menelas N.
通讯作者：
Pangalos, Menelas N.
影响因子：
11.2
作者：
Landau, Susan M.;Mintun, Mark A.;Joshi, Abhinay D.;Koeppe, Robert A.;Petersen, Ronald C.;Aisen, Paul S.;Weiner, Michael W.;Jagust, William J.
通讯作者：
Jagust, William J.
影响因子：
2
作者：
Bretz, Frank;Dette, Holger;Pinheiro, Jose C.
通讯作者：
Pinheiro, Jose C.
影响因子：
2.4
作者：
Gold, Michael;Alderton, Claire;Sawchak, Sharon
通讯作者：
Sawchak, Sharon
DOI：
10.1186/s13195-016-0178-x
发表时间：
2016-03-07
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Hölttä M;Dean RA;Siemers E;Mawuenyega KG;Sigurdson W;May PC;Holtzman DM;Portelius E;Zetterberg H;Bateman RJ;Blennow K;Gobom J
通讯作者：
Gobom J