Weill Cornell Medical College, Department of Psychiatry, Box 140, 525 East 68th St, New York, NY 10065, USA.
J Clin Psychiatry. 2011 Mar;72(3):331-40. doi: 10.4088/JCP.10r06669.
The evolution of trial design and analysis during the lifespan of psychopharmacology is examined.
The clinical trial methodology used to evaluate psychopharmacologic agents has evolved considerably over the past 6 decades. The first and most productive decade was characterized by case series, each with a small number of patients. These trials used nonstandardized clinical observation as outcomes and seldom had a comparison group. The crossover design became widely used to examine acute psychiatric treatments in the 1950s and 1960s. Although this strategy provided comparison data, it introduced problems in study implementation and interpretation. In 1962, the US Food and Drug Administration began to require "substantial evidence of effectiveness from adequate and well-controlled studies." Subsequent decades saw remarkable advances in clinical trial design, assessment, and statistical analyses. Standardized instruments were developed and parallel groups, double-blinding, and placebo controls became the benchmark. Sample sizes increased and data analytic procedures were developed that could accommodate the problems of attrition. Randomized withdrawal designs were introduced in the 1970s to examine maintenance therapies. Ethical principles for research became codified in the United States at that time. A wave of regulatory approvals of novel antipsychotics, antidepressants, and anticonvulsants came in the 1980s and 1990s, each based on data from randomized double-blind, parallel-group, placebo-controlled clinical trials. These trial designs often involved fixed-dose comparisons based, in part, on a greater appreciation that much of the benefit and harm in psychopharmacology was dose related.
Despite the progress in randomized controlled trial (RCT) design, the discovery of new mechanisms of action and blockbuster interventions has slowed during the past decade.
考察精神药理学发展过程中试验设计和分析的演变。
过去 60 年来，评估精神药物的临床试验方法有了很大的发展。最初和最富有成效的十年以病例系列为特征，每个病例系列都有少数患者。这些试验使用非标准化的临床观察作为结果，很少有对照组。交叉设计在 20 世纪 50 年代和 60 年代被广泛用于检查急性精神治疗。虽然这种策略提供了比较数据，但它在研究实施和解释方面引入了问题。1962 年，美国食品和药物管理局开始要求“从充分和良好控制的研究中获得实质性的有效性证据”。随后的几十年见证了临床试验设计、评估和统计分析的显著进展。开发了标准化工具，平行组、双盲和安慰剂对照成为基准。样本量增加，开发了数据分析程序，可以适应数据缺失的问题。随机撤药设计于 20 世纪 70 年代引入，以检查维持治疗。当时，美国制定了研究伦理原则。20 世纪 80 年代和 90 年代，一波新型抗精神病药、抗抑郁药和抗惊厥药的监管批准浪潮相继出现，每一种药物的批准都基于随机双盲、平行组、安慰剂对照临床试验的数据。这些试验设计通常涉及基于固定剂量的比较，部分原因是对精神药理学中大部分益处和危害与剂量有关的认识有所提高。
尽管在随机对照试验 (RCT) 设计方面取得了进展，但在过去十年中，新作用机制和重磅干预措施的发现速度有所放缓。
