Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Advanced Academic Programs, Regulatory Science, Johns Hopkins University, Rockville, Maryland; Center for Drug Evaluation and Research, Office of New Drugs, Division of Neurology Products, Food and Drug Administration, Silver Spring, Maryland.
Clin Ther. 2018 Jan;40(1):95-102.e2. doi: 10.1016/j.clinthera.2017.11.012. Epub 2017 Dec 19.
Biological drug products, or products derived from living cells, represent an increasingly important part of the pharmaceutical market. Despite this, little is known about how sponsors determine the dose to be studied in registrational trials or to be proposed in labeling for biologics. We examined how exposure-response and dose-response analyses were used to determine dosing in pivotal trials or the labeling for all biologics approved by the Center for Drug Evaluation and Research, the US Food and Drug Administration (FDA) between 2003 and 2016.
We extracted relevant characteristics of each biologic from its review package by FDA. We used descriptive statistics to characterize the rationale for the selected dose(s) in registration trials, with a particular focus on the role of exposure-response/dose-response analyses. We also examined how exposure-response/dose-response analyses were used to support the labeling dose and the basis for postmarketing requirements or commitments related to dose optimization.
A total of 79 biologics license applications were examined. Dose selection in registrational trials was more often attributed to clinical efficacy (73% of applications) than to clinical safety (42%). The dosing of products whose dose was apparently selected based on clinical efficacy was often (72%) determined by the dose-response relationship. In support of doses that were described in labeling, exposure-response analyses for efficacy were performed more commonly (53%) than dose-response analyses (21%). This trend was apparent after 2012.
This is the first study to summarize the justification of dose selection and the labeled dose of biologics approved by the FDA. Dose-response analyses have been often used as the rationale for dose selection of registrational studies, although exposure-response analyses are becoming more prevalent in support of the dosing guidelines in labeling.
生物药物产品，或源自活细胞的产品，代表了医药市场中越来越重要的一部分。尽管如此，对于赞助商如何确定注册试验中要研究的剂量或在生物制剂标签中提出的剂量，人们知之甚少。我们研究了在 2003 年至 2016 年间，美国食品和药物管理局（FDA）的药品评估和研究中心批准的所有生物制剂在关键性试验中或在标签中确定剂量的方法，包括使用暴露-反应和剂量-反应分析。
我们从 FDA 的审查包中提取了每个生物制剂的相关特征。我们使用描述性统计来描述注册试验中选定剂量的基本原理，特别关注暴露-反应/剂量-反应分析的作用。我们还研究了如何使用暴露-反应/剂量-反应分析来支持标签剂量以及与剂量优化相关的上市后要求或承诺的基础。
共检查了 79 种生物制品许可申请。注册试验中的剂量选择更多地归因于临床疗效（73%的申请）而不是临床安全性（42%）。显然基于临床疗效选择剂量的产品的给药通常（72%）由剂量-反应关系确定。在支持标签中描述的剂量方面，疗效的暴露-反应分析比剂量-反应分析更常见（53%比 21%）。这种趋势在 2012 年后很明显。
这是第一项总结 FDA 批准的生物制剂剂量选择和标签剂量的合理性的研究。尽管暴露-反应分析在支持标签中的剂量指南方面越来越普遍，但剂量反应分析经常被用作注册研究剂量选择的依据。
