Cleophas T J, Zwinderman A H
European Interuniversity College of Pharmaceutical Medicine, Dordrecht, Netherlands.
Clin Chem Lab Med. 2000 Dec;38(12):1217-23. doi: 10.1515/CCLM.2000.192.
The classical two-period crossover and two-parallel-groups designs for clinical drug trials are unable to answer many current scientific questions, and are sometimes ethically or financially difficult. For example, the classical designs do not allow the study of the effects of combined treatments and their interactions. Also, the generation of parallel data that are no more than a repetition of previous research is ethically debatable and in a sense a waste of money. Objectives are to identify what a classical clinical trial cannot manage, to summarize and discuss alternative trial designs that are helpful for such purposes.
A classical clinical trial cannot: (i) assess combined therapies, (ii) take historical data into account, (iii) safeguard ethics and efficacy during the course of long-term trials, (iv) study drugs, before well-established toxicity information is available, (v) account for the possibility of therapeutic equivalence between test and reference treatment, (vi) study multiple treatments in one trial, and (vii) adjust change scores for baseline levels. Alternative designs helpful for such purposes are respectively: (i) factorial designs, (ii) historical controls designs, (iii) group-sequential interim analysis designs, (iv) sequential designs for continuous monitoring, (v) therapeutic equivalence designs, (vi) multiple crossover-periods/multiple parallel-groups design, and (vii) increased precision designs through multivariate adjustment. Main problems include the increased risks of type I and type II errors and the loss of validity criteria.
Non-classical trial designs are reviewed. They offer relevant scientific, ethical, and financial advantages. The increased risks of type I and type II errors should be accounted for in the design stage of the trial.
临床药物试验的经典两阶段交叉设计和两平行组设计无法回答许多当前的科学问题，并且有时在伦理或经济方面存在困难。例如，经典设计不允许研究联合治疗的效果及其相互作用。此外，生成不过是先前研究重复的平行数据在伦理上存在争议，从某种意义上说也是资金的浪费。目的是确定经典临床试验无法处理的问题，总结并讨论有助于实现此类目的的替代试验设计。
经典临床试验无法：（i）评估联合疗法；（ii）考虑历史数据；（iii）在长期试验过程中保障伦理和疗效；（iv）在尚未获得充分的毒性信息之前研究药物；（v）考虑试验治疗与对照治疗之间治疗等效性的可能性；（vi）在一项试验中研究多种治疗方法；（vii）对基线水平调整变化分数。有助于实现此类目的的替代设计分别为：（i）析因设计；（ii）历史对照设计；（iii）成组序贯中期分析设计；（iv）连续监测的序贯设计；（v）治疗等效性设计；（vi）多交叉期/多平行组设计；（vii）通过多变量调整提高精度的设计。主要问题包括I型和II型错误风险增加以及有效性标准的丧失。
对非经典试验设计进行了综述。它们具有相关的科学、伦理和经济优势。在试验设计阶段应考虑I型和II型错误风险增加的问题。
