Wang Yehong, Zhu Rui, Xiao Jim, Davis John C, Mandema Jaap W, Jin Jin Y, Tang Meina T
Clinical Pharmacology, Genentech, Inc, South San Francisco, CA, USA.
Clinical Sciences, Genentech, South San Francisco, CA, USA.
J Clin Pharmacol. 2016 Jul;56(7):835-44. doi: 10.1002/jcph.668. Epub 2015 Dec 31.
The objective of this study was to assess the relationship between short-term and long-term treatment effects measured by the American College of Rheumatology (ACR) 50 responses and to assess the feasibility of predicting 6-month efficacy from short-term data. A rheumatoid arthritis (RA) database was constructed from 68 reported trials. We focused on the relationship between 3- and 6-month ACR50 treatment effects and developed a generalized nonlinear model to quantify the relationship and test the impact of covariates. The ΔACR50 at 6 months strongly correlated with that at 3 months, moderately correlated with that at 2 months, and only weakly correlated with results obtained at <2 months. A scaling factor that reflected the ratio of 6- to 3-month treatment effects was estimated to be 0.997, suggesting that the treatment effects at 3 months are approaching a "plateau." Drug classes, baseline Disease Activity Score in 28 Joints, and the magnitude of control arm response did not show significant impacts on the scaling factor. This work quantitatively supports the empirical clinical development paradigm of using 3-month efficacy data to predict long-term efficacy and to inform the probability of clinical success based on early efficacy readout.
本研究的目的是评估由美国风湿病学会（ACR）50反应所衡量的短期和长期治疗效果之间的关系，并评估根据短期数据预测6个月疗效的可行性。从68项报告的试验中构建了一个类风湿性关节炎（RA）数据库。我们重点关注3个月和6个月时ACR50治疗效果之间的关系，并开发了一个广义非线性模型来量化这种关系并测试协变量的影响。6个月时的ΔACR50与3个月时的ΔACR50高度相关，与2个月时的ΔACR50中度相关，而与小于2个月时获得的结果仅呈弱相关。反映6个月与3个月治疗效果之比的缩放因子估计为0.997，这表明3个月时的治疗效果正在接近一个“平台期”。药物类别、28个关节的基线疾病活动评分以及对照臂反应的幅度对缩放因子没有显著影响。这项工作从定量角度支持了基于3个月疗效数据来预测长期疗效并根据早期疗效读数判断临床成功概率的经验性临床开发模式。
