Background:Researchers often conduct small studies on testing a drug’s efficacy in off-label indications. If positive results from these exploratory studies are not followed up by larger, randomized, double-blinded trials, physicians cannot be sure of a drug’s clinical value. This may lead to off-label prescriptions of ineffective treatments. We aim to describe the way clinical studies fostered off-label prescription of the antipsychotic drug quetiapine (Seroquel).Methods:In this systematic meta-epidemiological analysis, we searched EMBASE, MEDLINE, Cochrane CENTRAL and PsycINFO databases and included clinical studies testing quetiapine for unapproved indications between May 1995 and May 2022. We then assessed the frequency with which publications providing low-level evidence suggesting efficacy of quetiapine for off-label indications was not followed up by large, randomized and double-blinded trials within 5 years.Results:In total, 176 published studies were identified that reported potential efficacy of quetiapine in at least 26 indications. Between 2000 and 2007, publication of exploratory studies suggesting promise for off-label indications rapidly outpaced publication of confirmatory trials. In the 24 indications with a minimum of 5 years of follow-up from the first positive exploratory study, 19 (79%) were not followed up with large confirmatory trials within 5 years. At least nine clinical practice guidelines recommend the use of quetiapine for seven off-label indications in which published confirmatory evidence is lacking.Conclusion:Many small, post-approval studies suggested the promise of quetiapine for numerous off-label indications. These findings generally went unconfirmed in large, blinded, randomized trials years after first being published. The imbalance of exploratory and confirmatory studies likely encourages ineffective off-label treatment.

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鼓励超说明书使用喹硫平的研究：系统的元流行病学分析

背景：研究人员经常进行小型研究来测试药物在适应症外的疗效。如果这些探索性研究的积极结果没有得到更大规模、随机、双盲试验的跟进，医生就无法确定药物的临床价值。这可能会导致标签外处方无效的治疗。我们的目的是描述临床研究促进抗精神病药物喹硫平（思瑞康）超说明书处方的方式。方法：在这项系统的元流行病学分析中，我们检索了 EMBASE、MEDLINE、Cochrane CENTRAL 和 PsycINFO 数据库，并纳入了测试喹硫平的临床研究1995 年 5 月至 2022 年 5 月之间未批准的适应症。然后，我们评估了提供低水平证据表明喹硫平对适应症外适应症有效的出版物在 5 年内未进行大型随机双盲试验的频率。结果：总共有 176 项已发表的研究报告了喹硫平在至少 26 种适应症中的潜在功效。2000 年至 2007 年间，探索性研究的发表表明对超说明书适应症的承诺迅速超过了验证性试验的发表。在自第一个积极探索性研究起至少随访 5 年的 24 种适应症中，有 19 种（79%）没有在 5 年内进行大型验证性试验的随访。至少九个临床实践指南建议使用喹硫平治疗七种标签外适应症，但缺乏已发表的证实性证据。结论：许多小型批准后研究表明喹硫平有望用于多种标签外适应症。这些发现在首次发表数年后通常没有在大型、盲法、随机试验中得到证实。探索性研究和验证性研究的不平衡可能会鼓励无效的标签外治疗。