Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda, 5601, Maryland, USA.
Stat Med. 2021 Nov 30;40(27):5983-6007. doi: 10.1002/sim.9001. Epub 2021 Apr 29.
Randomized vaccine trials are used to assess vaccine efficacy (VE) and to characterize the durability of vaccine-induced protection. If efficacy is demonstrated, the treatment of placebo volunteers becomes an issue. For COVID-19 vaccine trials, there is broad consensus that placebo volunteers should be offered a vaccine once efficacy has been established. This will likely lead to most placebo volunteers crossing over to the vaccine arm, thus complicating the assessment of long term durability. We show how to analyze durability following placebo crossover and demonstrate that the VE profile that would be observed in a placebo controlled trial is recoverable in a trial with placebo crossover. This result holds no matter when the crossover occurs and with no assumptions about the form of the efficacy profile. We only require that the VE profile applies to the newly vaccinated irrespective of the timing of vaccination. We develop different methods to estimate efficacy within the context of a proportional hazards regression model and explore via simulation the implications of placebo crossover for estimation of VE under different efficacy dynamics and study designs. We apply our methods to simulated COVID-19 vaccine trials with durable and waning VE and a total follow-up of 2 years.
随机疫苗试验用于评估疫苗的效力（VE），并描述疫苗诱导保护的持久性。如果证明了疗效，那么安慰剂志愿者的治疗就成为一个问题。对于 COVID-19 疫苗试验，人们普遍认为一旦确定了疗效，就应该为安慰剂志愿者提供疫苗。这可能导致大多数安慰剂志愿者转向疫苗组，从而使长期持久性的评估变得复杂。我们展示了如何在安慰剂交叉后分析持久性，并证明在安慰剂对照试验中观察到的 VE 特征可以在有安慰剂交叉的试验中恢复。无论交叉发生的时间如何，无论疗效特征的形式如何，这一结果都成立。我们只要求 VE 特征适用于新接种的人群，而不论接种时间如何。我们在比例风险回归模型的背景下开发了不同的方法来估计疗效，并通过模拟探索了安慰剂交叉对不同疗效动态和研究设计下 VE 估计的影响。我们将我们的方法应用于具有持久性和减弱性 VE 的模拟 COVID-19 疫苗试验，总随访时间为 2 年。
