Background:

Recently emerging results from a few placebo-controlled randomized trials of COVID-19 vaccines revealed estimates of 62%–95% relative reductions in risk of virologically confirmed symptomatic COVID-19 disease, over approximately 2-month average follow-up period. Additional safe and effective COVID-19 vaccines are needed in a timely manner to adequately address the pandemic on an international scale. Such safe and effective vaccines would be especially appealing for international deployment if they also have favorable stability, supply, and potential for implementation in mass vaccination campaigns. Randomized trials provide particularly reliable insights about vaccine efficacy and safety. While enhanced efficiency and interpretability can be obtained from placebo-controlled trials, in settings where their conduct is no longer possible, randomized non-inferiority trials may enable obtaining reliable evaluations of experimental vaccines through direct comparison with active comparator vaccines established to have worthwhile efficacy.

Methods:

The usual objective of non-inferiority trials is to reliably assess whether the efficacy of an experimental vaccine is not unacceptably worse than that of an active control vaccine previously established to be effective, likely in a placebo-controlled trial. This is formally achieved by ruling out a non-inferiority margin identified to be the minimum threshold for what would constitute an unacceptable loss of efficacy. This article not only investigates non-inferiority margins, denoted by δ, that address the usual objective of determining whether the experimental vaccine is “at least similarly effective to” the active comparator vaccine in the non-inferiority trial, but also develops non-inferiority margins, denoted by δ_o, intended to address the worldwide need for multiple safe and effective vaccines by satisfying the less stringent requirement that the experimental vaccine be “at least similarly effective to” an active comparator vaccine having efficacy that satisfies the widely accepted World Health Organization–Food and Drug Administration criteria for “worthwhile” vaccine efficacy.

Results:

Using the margin δ enables non-inferiority trials to reliably evaluate experimental vaccines that truly are similarly effective to an active comparator vaccine having any level of “worthwhile” efficacy. When active comparator vaccines have efficacy in the range of 50%–70%, non-inferiority trials designed to use the margin δ_o have appealing properties, especially for experimental vaccines having true efficacy of approximately 60%.

Conclusion:

Non-inferiority trials using the proposed margins may enable reliable randomized evaluations of efficacy and safety of experimental COVID-19 vaccines. Such trials often require approximately two- to three-fold the person-years follow-up than a placebo-controlled trial. This could be achieved, without substantive increases in sample size, by increasing the average duration of follow-up from 2 months to approximately 4–6 months, assuming efficacy of the active comparator vaccine has been reliably evaluated over that longer duration.

中文翻译：

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COVID-19疫苗试验：使用主动对照和非自卑性研究

背景：

一些安慰剂对照的COVID-19疫苗随机试验的最新研究结果表明，在大约2个月的平均随访期内，病毒学证实的有症状COVID-19疾病的风险相对降低了62％–95％。需要及时使用其他安全有效的COVID-19疫苗，以在国际范围内适当应对这一大流行病。如果此类安全有效的疫苗还具有良好的稳定性，供应量和在大规模疫苗接种运动中实施的潜力，则将特别吸引国际部署。随机试验提供了有关疫苗功效和安全性的特别可靠的见解。虽然可以从安慰剂对照试验中获得更高的效率和可解释性，但在不再可能进行的情况下，

方法：

非劣效性试验的通常目标是可靠地评估实验性疫苗的疗效是否比先前确立为有效的活性对照疫苗的疗效是否不可接受地差，这很可能是在安慰剂对照试验中。这是通过排除非劣质性界限而正式实现的，该劣势性界限是构成无法接受的功效丧失的最低阈值。本文不仅研究以δ表示的非劣效性边界，该非劣质性边界解决了确定非劣效性试验中实验疫苗是否与活性比较疫苗有效“至少相似”的通常目标，而且还发展了非劣效性边距，记为δ _ö旨在满足不太严格的要求，即实验疫苗必须“至少类似于”具有足以满足世界卫生组织-食品药品监督管理局要求的功效的活性比较疫苗，从而满足全球对多种安全有效疫苗的需求“有价值”疫苗效力的标准。

结果：

使用裕度δ可以使非劣效性试验可靠地评估实验性疫苗，这些疫苗实际上与具有任何“有价值”功效的活性比较疫苗有效类似。当活性对照疫苗中的50％-70％的范围内有功效的，非劣效性试验设计为使用余量δ _ø有无吸引人的性能，尤其是对于具有约60％的真实功效试验性疫苗。

结论：

使用建议的余量的非劣效性试验可能能够对实验性COVID-19疫苗的功效和安全性进行可靠的随机评估。与安慰剂对照试验相比，此类试验通常需要大约2至3倍的人年随访。可以通过将平均随访时间从2个月增加到大约4-6个月来实现，而无需大量增加样本量，前提是已在较长的持续时间内可靠地评估了活性比较疫苗的有效性。