Lantos John D, Wendler David, Septimus Edward, Wahba Sarita, Madigan Rosemary, Bliss Geraldine
Children's Mercy Bioethics Center, Department of Pediatrics, Children's Mercy Hospital, University of Missouri-Kansas City, Kansas City, MO, USA
National Institutes of Health Clinical Center, Bethesda, MD, USA.
Clin Trials. 2015 Oct;12(5):485-93. doi: 10.1177/1740774515597687. Epub 2015 Sep 15.
Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule (45 CFR 46, Subpart A) and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes "minimal risk," there are important practical implications: the institutional review board may then allow a waiver or alteration of the informed consent process; the study may be carried out in certain vulnerable populations; or the study may be reviewed by institutional review boards using an expedited process. However, it is unclear how institutional review boards should assess the risk levels of pragmatic clinical trials. Such trials typically compare existing, widely used medical therapies or interventions in the setting of routine clinical practice. Some of the therapies may be considered risky of themselves but the study comparing them may or may not add to that pre-existing level of risk. In this article, we examine the common interpretations of research regulations regarding minimal-risk classifications and suggest that they are marked by a high degree of variability and confusion, which in turn may ultimately harm patients by delaying or hindering potentially beneficial research. We advocate for a clear differentiation between the risks associated with a given therapy and the incremental risk incurred during research evaluating those therapies as a basic principle for evaluating the risk of a pragmatic clinical trial. We then examine two pragmatic clinical trials and consider how various factors including clinical equipoise, practice variation, research methods such as cluster randomization, and patients' perspectives may contribute to current and evolving concepts of minimal-risk determinations, and how this understanding in turn affects the design and conduct of pragmatic clinical trials.
负责监督研究的机构审查委员会必须根据一项名为《通用规则》（45 CFR 46，A部分）的联邦法规以及美国食品药品监督管理局在21 CFR 50中编纂的法规，对拟议研究的风险程度进行分类。如果机构审查委员会确定一项临床试验构成“最低风险”，则会产生重要的实际影响：机构审查委员会随后可能允许放弃或更改知情同意程序；该研究可能在某些弱势群体中进行；或者该研究可能由机构审查委员会采用快速程序进行审查。然而，尚不清楚机构审查委员会应如何评估务实临床试验的风险水平。此类试验通常在常规临床实践背景下比较现有的、广泛使用的医学疗法或干预措施。其中一些疗法本身可能被认为有风险，但比较它们的研究可能会增加或不会增加已有的风险水平。在本文中，我们研究了研究法规对最低风险分类的常见解释，并指出这些解释存在高度的变异性和混乱性，这反过来可能最终通过延迟或阻碍潜在有益的研究而伤害患者。我们主张将与特定疗法相关的风险与评估这些疗法的研究过程中产生的增量风险明确区分开来，作为评估务实临床试验风险的一项基本原则。然后，我们研究了两项务实临床试验，并考虑包括临床 equipoise、实践差异、聚类随机化等研究方法以及患者观点在内的各种因素如何可能促成当前和不断演变的最低风险判定概念，以及这种理解反过来如何影响务实临床试验的设计和实施。
