Influenza vaccine efficacy trials: a simulation approach to understand failures from the past.
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.
Institut de Statistique, Biostatistique et Sciences Actuarielles (ISBA), Université catholique de Louvain, Brussels, Belgium.|GSK Biologicals, Rixensart, Belgium.
Anne
A
Benoit
Institut de Statistique, Biostatistique et Sciences Actuarielles (ISBA), Université catholique de Louvain, Brussels, Belgium.
Catherine
C
Legrand
GSK Biologicals, Rixensart, Belgium.
Walthère
W
Dewé
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic / Q000379:methods / Q000706:statistics & numerical data*; D003198:Computer Simulation; D023381:Endpoint Determination / Q000706:statistics & numerical data; D058872:Epidemics / Q000517:prevention & control*; D006801:Humans; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015233:Models, Statistical; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000276:immunology; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data*; D012621:Seasons; D013997:Time Factors; D017211:Treatment Failure
D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines
clinical trials; seasonal influenza; simulation; vaccine efficacy