PDF(Pubmed)
Abstract：
Two significant pivotal trials are usually required for a new drug approval by a regulatory agency. This standard requirement is known as the two-trial paradigm. However, several authors have questioned why we need exactly two pivotal trials, what statistical error the regulators are trying to protect against, and potential alternative approaches. Therefore, it is important to investigate these questions to better understand the regulatory decision-making in the assessment of drugs\' effectiveness. It is common that two identically designed trials are run solely to adhere to the two-trial rule. Previous work showed that combining the data from the two trials into a single trial (one-trial paradigm) would increase the power while ensuring the same level of type I error protection as the two-trial paradigm. However, this is true only under a specific scenario and there is little investigation on the type I error protection over the whole null region. In this article, we compare the two paradigms by considering scenarios in which the two trials are conducted in identical or different populations as well as with equal or unequal size. With identical populations, the results show that a single trial provides better type I error protection and higher power. Conversely, with different populations, although the one-trial rule is more powerful in some cases, it does not always protect against the type I error. Hence, there is the need for appropriate flexibility around the two-trial paradigm and the appropriate approach should be chosen based on the questions we are interested in.
摘要：
监管机构批准新药通常需要两项重要的关键试验。这一标准要求被称为两次试验范式。然而,几位作者质疑为什么我们需要两个关键的试验，监管机构试图防止哪些统计错误，和潜在的替代方法。因此,调查这些问题以更好地理解药物有效性评估中的监管决策非常重要。通常，两个设计相同的试验仅为了遵守两次试验规则而进行。先前的工作表明，将两次试验的数据合并为一次试验（一次试验范式）将增加功率，同时确保与两次试验范式相同的I型错误保护水平。然而,这仅在特定场景下是正确的，并且对整个null区域上的类型I错误保护的调查很少。在这篇文章中,我们通过考虑两项试验在相同或不同人群中进行以及规模相等或不相等的情况来比较两种范式.人口相同，结果表明，单次试验提供了更好的I型错误保护和更高的功率。相反，不同的人口，尽管一审规则在某些情况下更强大，它并不总是防止类型I错误。因此，围绕两次审判范式需要适当的灵活性，应该根据我们感兴趣的问题选择适当的方法。
