ABSTRACT

Because of structural complexity, a “biosimilar” will not be exactly the same as its reference biologic treatment, but is required to be equivalent in all relevant attributes, including efficacy. Therapeutic equivalence is often assessed at a single time point and trajectory up to that time point ignored. This paper describes a measure to assess therapeutic equivalence in rheumatoid arthritis that takes into account both the trajectory and the peak efficacy. This time-response measure is compared with the standard single-time-point measure via simulations based on recent clinical trials of biosimilars. Scenarios can be constructed where the single-time-point measure is more sensitive in detection of non-equivalence, particularly where the time-response curve is not monotone; but for a variety of trajectories the time-response measure has lower Type II error rate (higher power) for a given Type I error rate. Performance is adversely affected by missing data for both measures. A limitation of the time-response measure is that it assumes a two-parameter exponential model for the trajectory of efficacy over time. Results under poor model fit are also presented. Where similarity of clinical outcome over time is a concern, the time-response measure should be considered when comparing a biosimilar and its reference product.

摘要

由于结构的复杂性，“生物仿制药”与其参考生物治疗不完全相同，但需要在所有相关属性（包括疗效）上相同。治疗等效性通常在单个时间点进行评估，并且忽略到该时间点的轨迹。本文描述了一种评估类风湿性关节炎治疗等效性的措施，该措施同时考虑了轨迹和峰值疗效。通过基于最近生物仿制药临床试验的模拟，将该时间响应测量与标准单时间点测量进行比较。可以构建单时间点测量在检测非等效性方面更敏感的场景，特别是在时间响应曲线不是单调的情况下；但是对于各种轨迹，对于给定的 I 类错误率，时间响应测量具有较低的 II 类错误率（更高的功率）。两种度量的数据缺失都会对性能产生不利影响。时间响应测量的一个限制是它假设了一个两参数指数模型，用于随时间推移的功效轨迹。还给出了模型拟合不佳的结果。当关注临床结果随时间的相似性时，在比较生物仿制药及其参考产品时，应考虑时间反应测量。还给出了模型拟合不佳的结果。当关注临床结果随时间的相似性时，在比较生物仿制药及其参考产品时，应考虑时间反应测量。还给出了模型拟合不佳的结果。当关注临床结果随时间的相似性时，在比较生物仿制药及其参考产品时，应考虑时间反应测量。