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首页> 外文期刊>The EPMA journal. >Suggestions for improving the design of clinical trials in multiple sclerosis—results of a systematic analysis of completed phase III trials
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Suggestions for improving the design of clinical trials in multiple sclerosis—results of a systematic analysis of completed phase III trials

机译：提出改善多发性硬化症的临床试验设计的建议 - 完成第三阶段试验的系统分析结果

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This manuscript reviews the primary and secondary endpoints of pivotal phase III trials with immunomodulatory drugs in multiple sclerosis (MS). Considering the limitations of previous trial designs, we propose new standards for the planning of clinical trials, taking into account latest insights into MS pathophysiology and patient-relevant aspects. Using a systematic overview of published phase III (pivotal) trials performed as part of application for drug market approval, we evaluate the following characteristics: trial duration, number of trial participants, comparators, and endpoints (primary, secondary, magnetic resonance imaging outcome, and patient-reported outcomes). From a patient perspective, the primary and secondary endpoints of clinical trials are only partially relevant. High-quality trial data pertaining to efficacy and safety that stretch beyond the time frame of pivotal trials are almost non-existent. Understanding of long-term benefits and risks of disease-modifying MS therapy is largely lacking. Concrete proposals for the trial designs of relapsing (remitting) multiple sclerosis/clinically isolated syndrome, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis (e.g., study duration, mechanism of action, and choice of endpoints) are presented based on the results of the systematic overview. Given the increasing number of available immunotherapies, the therapeutic strategy in MS has shifted from a mere “relapse-prevention” approach to a personalized provision of medical care as to the choice of the appropriate drugs and their sequential application over the course of the disease. This personalized provision takes patient preferences as well as disease-related factors into consideration such as objective clinical and radiographic findings but also very burdensome symptoms such as fatigue, depression, and cognitive impairment. Future trial designs in MS will have to assign higher relevance to these patient-reported outcomes and will also have to implement surrogate measures that can serve as predictive markers for individual treatment response to new and investigational immunotherapies. This is an indispensable prerequisite to maximize the benefit of individual patients when participating in clinical trials. Moreover, such appropriate trial designs and suitable enrolment criteria that correspond to the mode of action of the study drug will facilitate targeted prevention of adverse events, thus mitigating risks for individual study participants.
机译：本手稿审查多发性硬化症（MS）中具有免疫调节药物的枢转期III试验的主要和次要终点。考虑到以前试验设计的局限性，我们提出了临床试验规划的新标准，考虑到了对MS病理生理学和患者相关方面的最新见解。使用作为药物市场批准的申请的一部分进行的发布阶段III（关键）试验的系统概述，我们评估以下特征：试验期限，试验参与者数量，比较器和终点（初级，二级，磁共振成像结果，和患者报告的结果）。从患者的角度来看，临床试验的主要和次要终点仅是部分相关的。与效力和安全有关的高质量试验数据，延伸超越关键试验的时间框架几乎是不存在的。对长期益处和疾病修饰的风险的理解在很大程度上缺乏。基于结果，提出了基于结果，提出了复发式（剩余）多发性硬化症/临床分离综合征，初级进展多发性硬化症（例如，研究持续时间，行动机制和终点的选择）的初级进展多发性综合征系统概述。鉴于可用免疫疗法数量越来越多，MS的治疗策略已从仅仅是“复发预防”的方法转移到个性化提供医疗服务，以便在疾病过程中选择适当的药物及其顺序施用。这种个性化的拨款考虑了患者偏好以及疾病相关因素，例如客观的临床和放射线摄影结果，但也非常繁琐，抑郁和认知障碍等繁重症状。 MS的未来试验设计将不得不分配与这些患者报告的结果更高的相关性，并且还必须实施可用作对新和调查免疫治疗的个体治疗反应的预测标记的替代措施。这是在参与临床试验时最大限度地提高个体患者的不可或缺的先决条件。此外，这种适当的试验设计和适当的入学标准对应于研究药物的作用方式，促进有针对性的防止不良事件，从而减轻个体研究参与者的风险。

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