The failure of placebo-controlled studies
The failure of placebo-controlled studies
复制标题
DOI：
10.1016/s0924-977x(98)00050-9
复制
发表时间：
1999-03-01
影响因子：
5.6
通讯作者：
Montgomery, SA
中科院分区：
文献类型：
--
作者：
Montgomery, SA
近年来，越来越多的临床试验来测试新的潜在治疗的疗效，但无论是新的治疗还是已确定的参考药物，都未能证明与安慰剂的差异。在一系列精神疾病中观察到的对安慰剂的应答率的上升并没有被对药物的应答率的上升所抵消，并且小的效应量使得难以建立显著的差异。许多因素被认为是导致安慰剂反应上升或效应量较小的原因。这些因素包括研究人群随时间的差异、研究者行为的变化以及试验设计的失败，纳入更多轻度疾病或疾病具有波动性病程的患者被认为可能会增加安慰剂应答率。需要密切关注患者的选择，包括诊断、严重程度和是否存在混杂的合并症，如酗酒、人格障碍或短暂抑郁症。在一些中心，安慰剂反应的增加与安慰剂反应的变异性增加有关。一些研究中心能够选择适当的患者进行研究，以证明参考治疗和安慰剂的分离，而其他研究中心则不能，这表明更仔细地选择研究者很重要。选择应该基于他们的经验，他们以前的学习记录，以及他们接受培训的能力。纳入参考治疗组为判断各中心的性能提供了一种有用的方法。排除偏心中心，未能达到预定的性能标准，如未能分开的参考治疗安慰剂，可以considered.Trial设计需要有足够的资格的研究人群，并充分注意诊断，最低严重程度和合并症在进入。在排除伴随的显性或隐性心理治疗和减少不必要的治疗接触方面需要更加谨慎，这些接触在某些协议中不知不觉地增加了。确定既往疾病稳定、明确残疾且入组时严重程度最低的患者可能会大幅降低安慰剂反应，并增加研究的效应量和把握度。还应考虑联合用药的可能影响。认为纳入安慰剂导入期没有帮助，应采用更好的统计技术，以最大限度地提高研究的敏感性，并增加检验疗效的机会。(C)1999年Elsevier Science B.V./ ECNP。All rights reserved.
In recent years an increasing number of clinical trials to test the efficacy of new potential treatments have failed to demonstrate a difference from placebo for either the new treatment or for an established reference drug. A rise in the response rate to placebo observed in a range of psychiatric disorders has not been paralleled by a rise in the response to drug and small effect sizes make it difficult to establish significant differences. A number of factors are thought to contribute to the rising placebo response or the smaller effect sizes. These include differences over time in the populations studied, changes in investigator behaviour, and failures of trial design.The inclusion of a greater number of patients with mild disorder or whose disorder has a fluctuating course is thought likely to increase the placebo response rates. Close attention needs to be paid to patient selection in terms of diagnosis, severity and absence of confounding comorbidity such as alcoholism, personality disorders or brief depression.The rising placebo response is associated with an increasing variability of placebo response seen in some centres. The ability of some centres to select appropriate patients for studies to demonstrate a separation of reference treatment and placebo and the inability of other centres suggests that a more careful selection of investigators is important. Selection should be based on their experience, their record from previous studies, and their aptitude for being trained. The inclusion of a reference treatment arm provides a useful means to judge the performance of individual centres. The exclusion of eccentric centres that fail to reach predetermined performance criteria, such as a failure to separate reference treatment from placebo, may be considered.Trial designs need to qualify adequately the study population and pay sufficient attention to diagnosis, minimum severity and comorbidity at entry. Greater care is needed in excluding concomitant overt or covert psychotherapy and in reducing the unnecessary therapeutic contact that has been increased unwittingly by some protocols. Identifying patients with prior stability of illness, with clear disability, and with a minimum severity at entry is likely to lower the placebo response substantially and increase the effect size and power of the study. The possible influence of comedication should also be considered. The inclusion of a placebo run in period is considered unhelpful and the use of better statistical techniques should be adopted to maximise the sensitivity of the study and increase the chances of testing efficacy. (C) 1999 Elsevier Science B.V./ECNP. All rights reserved.