Athauda Dilan, Foltynie Thomas
Sobell Department of Motor Neuroscience, UCL Institute of Neurology & The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, United Kingdom.
Parkinsonism Relat Disord. 2016 Nov;32:1-11. doi: 10.1016/j.parkreldis.2016.07.019. Epub 2016 Jul 31.
Despite the wealth of encouraging data from numerous compounds that demonstrate "neuroprotection" in pre-clinical studies of Parkinson's disease, and despite numerous clinical trials, to date, no intervention has been demonstrated to able to modify the course of disease progression. While this "failure to translate" is likely due to numerous factors including our incomplete understanding of the pathogenic mechanisms underlying PD together with excessive reliance on data from the toxin-based animal models of PD, here we will discuss the "structural issues" pertaining to inadequate clinical trial design, selection of inappropriate endpoints and poor patient selection which are often not addressed following failed disease modification trials. Future directions to overcome these challenges such as reducing the heterogeneity of patient cohorts, identifying and utilising a pre-diagnostic population, embracing a personalised medicine approach and utilising novel trial designs may be required to ultimately fulfil the goal of conclusively demonstrating evidence of disease modification.
尽管众多化合物在帕金森病临床前研究中显示出“神经保护”作用，有大量令人鼓舞的数据，且尽管进行了大量临床试验，但迄今为止，尚无干预措施被证明能够改变疾病进展过程。虽然这种“转化失败”可能是由于多种因素造成的，包括我们对帕金森病潜在致病机制的不完全理解，以及过度依赖基于毒素的帕金森病动物模型的数据，但在此我们将讨论与临床试验设计不足、终点选择不当和患者选择不佳相关的“结构问题”，而这些问题在疾病修饰试验失败后往往未得到解决。可能需要未来的方向来克服这些挑战，例如减少患者队列的异质性、识别和利用诊断前人群、采用个性化医疗方法以及利用新颖的试验设计，以最终实现确凿证明疾病修饰证据这一目标。
