Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA.
Clin Infect Dis. 2011 Jun;52 Suppl 7:S469-76. doi: 10.1093/cid/cir162.
Over the past decade, the United States has witnessed an epidemic of acute bacterial skin and skin-structure infections (ABSSSIs) caused primarily by community-acquired methicillin-resistant Staphylococcus aureus. To address this medical need as well as the ongoing threat of increasing resistance, new antibiotics are being developed. Clinical trials involving patients with complicated ABSSSI are being implemented to understand the efficacy and safety of these new antibiotic agents. Because antibiotics clearly have an effect on the resolution of the majority of these infections, placebo-controlled trials have been replaced by noninferiority studies. However, to conduct noninferiority trials a noninferiority margin must be determined on the basis of the effect size of the comparator antibiotic. The lack of modern-day placebo-controlled studies of ABSSSI makes determining effect size/noninferiority margin--and as a result, trial design--challenging. The US Food and Drug Administration (FDA) in collaboration with the Foundation for the National Institutes of Health (FNIH) have been working hard to resolve these issues and develop a new guidance to aid investigators in the conduct of these trials. In this article, we first review the 1998 guidance and its shortcomings. Next, we address the ongoing discussion of the new 2010 guidance as we understand it, along with its perceived strengths and weaknesses. Throughout this process, we wish to emphasize that the continued development of antibiotics is essential. Thus, we hope that as the FDA and FNIH move forward they will strike a balance between "The Perfect" statistical solution and "The Good" practical clinical realities.
在过去的十年中，美国见证了主要由社区获得性耐甲氧西林金黄色葡萄球菌引起的急性细菌性皮肤和皮肤结构感染（ABSSSI）的流行。为了解决这一医疗需求以及不断增加的耐药性威胁，正在开发新的抗生素。正在对患有复杂 ABSSSI 的患者进行临床试验，以了解这些新抗生素药物的疗效和安全性。由于抗生素显然对大多数这些感染的消退有影响，因此已经用非劣效性研究取代了安慰剂对照试验。然而，为了进行非劣效性试验，必须根据比较抗生素的效应大小来确定非劣效性边界。由于缺乏现代 ABSSSI 的安慰剂对照研究，因此确定效果大小/非劣效性边界（进而确定试验设计）具有挑战性。美国食品和药物管理局（FDA）与美国国立卫生研究院基金会（FNIH）合作，一直在努力解决这些问题，并制定新的指导方针，以帮助研究人员进行这些试验。在本文中，我们首先回顾了 1998 年的指导意见及其缺点。接下来，我们讨论了我们所理解的正在进行的新 2010 年指导意见的讨论，以及它被认为的优点和缺点。在整个过程中，我们希望强调继续开发抗生素是至关重要的。因此，我们希望随着 FDA 和 FNIH 的前进，他们将在“完美”的统计解决方案和“良好”的实际临床现实之间取得平衡。
