Smith Michael K, Jones Ieuan, Morris Mark F, Grieve Andrew P, Tan Keith
Clinical Statistics for Clinical Sciences, Pfizer Global Research and Development, Sandwich, Kent, UK.
Pharm Stat. 2006 Jan-Mar;5(1):39-50. doi: 10.1002/pst.198.
With increased costs of drug development the need for efficient studies has become critical. A key decision point on the development pathway has become the proof of concept study. These studies must provide clear information to the project teams to enable decision making about further developing a drug candidate but also to gain evidence that any effect size is sufficient to warrant this development given the current market environment. Our case study outlines one such proof of concept trial where a new candidate therapy for neuropathic pain was investigated to assess dose-response and to evaluate the magnitude of its effect compared to placebo. A Normal Dynamic Linear Model was used to estimate the dose-response--enforcing some smoothness in the dose-response, but allowing for the fact that the dose-response may be non-monotonic. A pragmatic, parallel group study design was used with interim analyses scheduled to allow the sponsor to drop ineffective doses or to stop the study. Simulations were performed to assess the operating characteristics of the study design. The study results are presented. Significant cost savings were made when it transpired that the new candidate drug did not show superior efficacy when compared placebo and the study was stopped.
随着药物研发成本的增加，开展高效研究的需求变得至关重要。研发途径中的一个关键决策点已成为概念验证研究。这些研究必须为项目团队提供清晰的信息，以便就进一步开发候选药物做出决策，同时还要获取证据，证明在当前市场环境下，任何效应大小都足以支持这种开发。我们的案例研究概述了一项这样的概念验证试验，其中对一种用于神经性疼痛的新候选疗法进行了研究，以评估剂量反应，并与安慰剂相比评估其效应的大小。使用了一个正态动态线性模型来估计剂量反应——在剂量反应中强制保持一定的平滑性，但考虑到剂量反应可能是非单调的这一事实。采用了实用的平行组研究设计，并安排了中期分析，以便申办者能够放弃无效剂量或停止研究。进行了模拟以评估研究设计的操作特性。给出了研究结果。当发现新候选药物与安慰剂相比未显示出卓越疗效且研究停止时，节省了大量成本。
