Schulz Constanze, Timm Jürgen, Cordes Joachim, Gründer Gerhard, Mühlbauer Bernd, Rüther Eckart, Heinze Martin
Competence Center for Clinical Trials Bremen, University of Bremen, Bremen, Germany
Competence Center for Clinical Trials Bremen, University of Bremen, Bremen, Germany.
Clin Trials. 2016 Jun;13(3):251-9. doi: 10.1177/1740774516639910. Epub 2016 Mar 25.
The 'gold standard' for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians' preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types.
The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients' needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia.
In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians' preferences for specific drugs used for the respective patients were analysed.
The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient-drug interaction, this design should prove particularly useful.
临床研究的“金标准”是通常比较特定治疗方法的随机对照试验。如果科学研究扩展到对包括各种治疗方法的每种策略进行比较，研究问题就会变得越来越复杂。精神病学界的策略辩论是我们新设计的出发点。第二代抗精神病药物是治疗精神分裂症的首选疗法，这一点已被广泛接受。然而，在最近的随机对照试验中，并未证明它们总体上优于第一代抗精神病药物。此外，我们越来越意识到，随机对照试验的实验条件，如欧洲首发精神分裂症试验和临床抗精神病药物干预有效性第一阶段研究中的条件，可能不适用于精神科治疗。患者群体的高度异质性导致日常临床认知与随机对照试验结果之间存在差异。精神分裂症最新抗精神病药物成本效用研究中以患者为导向的方法反映了日常临床实践。然而，结果高度依赖于医生的偏好。这里描述的设计目标是在随机对照试验和临床研究（如精神分裂症最新抗精神病药物成本效用研究）之间走一条中间道路，结合两种研究类型的优点。
思路是首先将两个治疗组进行随机分组，每个治疗组由一种第一代抗精神病药物和一种第二代抗精神病药物组成，随后让研究人员决定最适合患者需求的一组，然后将该选定组中的一种药物（第一代抗精神病药物或第二代抗精神病药物）进行随机分配。这个想法首先在临床试验“抗精神病药物策略研究”中得以实施，该试验采用随机设计比较两种不同策略的疗效和安全性：在精神分裂症患者中使用第一代抗精神病药物（氟哌啶醇和三氟噻吨）或第二代抗精神病药物（奥氮平、阿立哌唑和喹硫平）。
在抗精神病药物策略研究过程中，证明了这种设计的可行性。新设计的各个方面都得以实施：随机化过程、研究人员以及患者的反应记录和药物后勤经验。此外，在实施该设计时，我们可以研究其理论特性。分析了医生对用于各自患者的特定药物的偏好。
以患者为导向的随机化理念可以推广。鉴于患者 - 药物相互作用的异质性和复杂性，这种设计应该会特别有用。
