Systematic Review of Measures of Clinical Significance Employed in Randomized Controlled Trials of Drugs for Dementia
Systematic Review of Measures of Clinical Significance Employed in Randomized Controlled Trials of Drugs for Dementia
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DOI：
10.1111/j.1532-5415.2008.02122.x
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发表时间：
2009-03-01
影响因子：
6.3
通讯作者：
Fergusson, Dean
中科院分区：
文献类型：
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作者：
Molnar, Frank J.;Man-Son-Hing, Malcolm;Fergusson, Dean
在痴呆症药物研究中定义结果测量的临床意义（临床重要性）的阈值的能力对于确定患者和家庭认为值得花费和值得冒药物副作用（即，临床重要性对于开始使用此类药物时的知情同意至关重要）。药物试验样本量计算（如果研究有把握检测临床重要差异）以及决定是否应接受处方集上的药物并应获得资助，也需要临床意义的保留。为了更好地了解在痴呆药物研究中采用了哪些具有临床意义的措施，对胆碱酯酶抑制剂和美金刚在阿尔茨海默病、血管性痴呆、混合性痴呆和轻度认知障碍受试者中的双盲随机对照试验（RCT）进行了系统评价。在审查的57项痴呆症药物随机对照试验中，只有46%讨论了其结果的临床意义。最常引用的临床意义指标是阿尔茨海默病评估量表-认知子量表的4分变化和整体量表的变化。大多数具有临床意义的指标是基于意见的。只有一项研究从经验上衡量了患者对临床意义阈值的看法。尽管对试验结果的解释和是否在临床实践中采用试验结果的决定至关重要，但以患者和患者为中心的临床意义指标尚未得到充分研究并整合到痴呆症药物RCT中。建议在CONSORT集团（www.consort-statement.org）等组织发布的研究标准中更加强调临床重要性的讨论。药物处方集审查委员会和许可机构（例如，美国食品药品监督管理局、欧洲药品评价局、加拿大卫生部）应考虑要求对他们审查的药物进行临床意义评估。为了推动这一领域的发展，资助机构应该考虑发起提案请求，重点是确定痴呆症研究中采用的结果指标的最小临床重要差异（MCID）。一旦MCID的经验数据可用，那么这些资助机构应该考虑支持一个共识会议，以审查和选择痴呆症研究中具有临床重要性的最佳措施。本文提出了一个初步的组织框架的临床意义的措施，以促进这样一个共识论坛的工作。
The ability to define thresholds for the clinical significance (clinical importance) of outcome measures in dementia drug research is critical to determining the changes on outcome measures that patients and families would consider worth the cost and worth risking the side effects of medications (i.e., clinical importance is central to informed consent when starting such medications). Thresholds for clinical significance are also required for drug trial sample size calculation (if the studies are to be powered to detect clinically important difference) and for decisions regarding whether medications should be accepted on formularies and should be funded. To better understand what measures of clinical significance have been employed in dementia drug research, a systematic review was performed of double-blind randomized controlled trials (RCTs) of cholinesterase inhibitors and memantine in subjects with Alzheimer's disease, vascular dementia, mixed dementia, and mild cognitive impairment. Of the 57 dementia drug RCTs reviewed, only 46% discussed the clinical significance of their results. The most commonly cited measures of clinical significance were a 4-point change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale and changes on global scales. The majority of measures of clinical significance were opinion based. Only one study empirically measured patient perspective regarding thresholds for clinical significance. Despite being central to the interpretation of trial results and to decisions regarding whether to employ trial findings in clinical practice, patient- and caregiver-centered measures of clinical significance have not been adequately studied and integrated into dementia drug RCTs. It is recommended that discussions of clinical importance receive greater emphasis in research standards published by organizations such as the CONSORT group (www.consort-statement.org). Drug formulary review committees and licensing agencies (e.g., U.S. Food and Drug Administration, European Agency for the Evaluation of Medicinal Products, Health Canada) should consider requiring an assessment of clinical significance of the drugs they review. To move this field forward, funding agencies should consider initiating requests for proposals focused on the determination of the minimally clinically important difference (MCID) of outcome measures employed in dementia research. Once empirical data on MCIDs are available, then these funding agencies should consider supporting a consensus conference to review and select the optimal measures of clinical importance in dementia research. A preliminary organizational framework of measures of clinical significance is presented in this article to facilitate the work of such a consensus forum.