Benoit Anne, Legrand Catherine, Dewé Walthère
Institut de Statistique, Biostatistique et Sciences Actuarielles (ISBA), Université catholique de Louvain, Brussels, Belgium.
GSK Biologicals, Rixensart, Belgium.
Pharm Stat. 2015 Jul-Aug;14(4):294-301. doi: 10.1002/pst.1685. Epub 2015 Apr 30.
The success of a seasonal influenza vaccine efficacy trial depends not only upon the design but also upon the annual epidemic characteristics. In this context, simulation methods are an essential tool in evaluating the performances of study designs under various circumstances. However, traditional methods for simulating time-to-event data are not suitable for the simulation of influenza vaccine efficacy trials because of the seasonality and heterogeneity of influenza epidemics. Instead, we propose a mathematical model parameterized with historical surveillance data, heterogeneous frailty among the subjects, survey-based heterogeneous number of daily contact, and a mixed vaccine protection mechanism. We illustrate our methodology by generating multiple-trial data similar to a large phase III trial that failed to show additional relative vaccine efficacy of an experimental adjuvanted vaccine compared with the reference vaccine. We show that small departures from the designing assumptions, such as a smaller range of strain protection for the experimental vaccine or the chosen endpoint, could lead to smaller probabilities of success in showing significant relative vaccine efficacy.
季节性流感疫苗效力试验的成功不仅取决于设计，还取决于年度流行特征。在此背景下，模拟方法是评估各种情况下研究设计性能的重要工具。然而，由于流感流行的季节性和异质性，传统的模拟事件发生时间数据的方法不适用于流感疫苗效力试验的模拟。相反，我们提出了一个数学模型，该模型由历史监测数据、受试者之间的异质性脆弱性、基于调查的每日接触异质性数量以及混合疫苗保护机制进行参数化。我们通过生成类似于一项大型III期试验的多次试验数据来说明我们的方法，该试验未能显示出与参考疫苗相比，实验性佐剂疫苗具有额外的相对疫苗效力。我们表明，与设计假设的微小偏差，例如实验疫苗的毒株保护范围较小或所选终点，可能会导致显示出显著相对疫苗效力的成功概率较小。
