The role of basket trials in drug development for neurodegenerative disorders.
The role of basket trials in drug development for neurodegenerative disorders.
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DOI：
10.1186/s13195-022-01015-6
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发表时间：
2022-05-25
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神经退行性疾病（NDD）的药物开发是一项长期，复杂和昂贵的事业。需要优化NDD药物开发的方法。篮式试验已广泛应用于肿瘤学，并已被美国食品药品监督管理局作为提高药物开发效率的一种手段加以推广。我们回顾了过去10年在clinicaltrials.gov上注册的NDD临床试验。我们确定了59个篮子试验，评估治疗对试验中一种以上NDD的影响。其中41项试验涉及25种药物，用于治疗NDD的症状，如运动障碍、低血压或精神病。其中18项试验评估了14种疾病修饰疗法;主要目标是线粒体功能，tau生物学或α-突触核蛋白聚集。篮式试验在II期最常见，但已在I期、III期和IV期进行。网篮试验的持续时间和尺寸因其开发阶段和试验目的而存在很大差异。帕金森病是对症药物篮子试验中最常见的疾病，阿尔茨海默病是疾病修饰疗法篮子试验中最常见的疾病。大多数对症药物的篮子试验由制药公司申办（41项试验中的29项）;同样，大多数调查篮子试验中DMT的篮子试验由生物制药行业申办（11/17项试验）。篮子试验可以通过减少试验实施中的冗余、加强招募、共享安慰剂组以及使用与NDD治疗作用机制相关的生物标志物来提高药物开发效率。在过去10年进行的同一试验中，包含多个NDD的篮子试验相对较少。使用篮子试验策略可能代表了一个机会，以提高药物开发计划的效率，以治疗NDD。
Drug development for neurodegenerative disorders (NDDs) is a long, complex, and expensive enterprise. Methods to optimize drug development for NDDs are needed. Basket trials have been widely used in oncology and have been promoted by the Food and Drug Administration as a means of enhancing the efficiency of drug development. We reviewed clinical trials for NDDs registered on clinicaltrials.gov in the past 10 years. We identified 59 basket trials assessing the impact of treatment on more than one NDD in the trial. Forty-one of the trials were for 25 agents addressing symptoms of NDD such as motor impairment, hypotension, or psychosis. Eighteen of the trials assessed 14 disease-modifying therapies; the principal targets were mitochondrial function, tau biology, or alpha-synuclein aggregation. Basket trials are most common in phase 2 but have been conducted in phase 1, phase 3, and phase 4. The duration and size of the basket trials are highly variable depending on their developmental phase and the intent of the trial. Parkinson’s disease was the most common disorder included in basket trials of symptomatic agents, and Alzheimer’s disease was the most common disorder included in basket trials of disease-modifying therapies. Most of the basket trials of symptomatic agents were sponsored by pharmaceutical companies (29 of 41 trials); similarly, most of the basket trials investigating DMTs in basket trials were sponsored by the biopharmaceutical industry (11/17 trials). Basket trials may increase drug development efficiency by reducing redundancy in trial implementation, enhancing recruitment, sharing placebo groups, and using biomarkers relevant to the mechanism of action of the treatment across NDDs. There have been relatively few basket trials including multiple NDDs in the same trial conducted over the past 10 years. The use of the basket trial strategy may represent an opportunity to increase the efficiency of development programs for agents to treat NDDs.
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