Assessing vaccine durability in randomized trials following placebo crossover
Assessing vaccine durability in randomized trials following placebo crossover
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DOI：
10.1002/sim.9001
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发表时间：
2021-04-29
影响因子：
2
通讯作者：
Follmann, Dean
中科院分区：
文献类型：
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作者：
Fintzi, Jonathan;Follmann, Dean
随机疫苗试验用于评估疫苗效力（VE）并表征疫苗诱导保护的持久性。如果疗效得到证实，安慰剂志愿者的治疗就成了一个问题。对于COVID-19疫苗试验，广泛的共识是，一旦确定有效性，就应该向安慰剂志愿者提供疫苗。这可能导致大多数安慰剂志愿者交叉至疫苗组，从而使长期耐久性评估复杂化。我们展示了如何分析安慰剂交叉后的耐久性，并证明在安慰剂对照试验中观察到的VE曲线在安慰剂交叉试验中是可恢复的。无论交叉发生在何时，该结果均成立，并且未对疗效特征的形式进行假设。我们只要求VE概况适用于新接种疫苗的人，而不论接种疫苗的时间。我们开发了不同的方法来估计的比例风险回归模型的背景下的疗效，并通过模拟的影响，安慰剂交叉估计VE不同的疗效动力学和研究设计探索。我们将我们的方法应用于模拟COVID-19疫苗试验，具有持久和减弱的VE，总随访时间为2年。
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.