Equipoise and the research integrity of clinical trials

描述（由申请人提供）：我们最近证明，临床试验中对研究完整性的主要威胁可能是由于违反了平衡或“不确定性原则”，这是几乎整个人体实验系统所依据的基本原则。 这一原则规定，只有当对哪种试验治疗对患者最有益存在实质性不确定性时，患者才应入组随机对照试验（RCT）。 我们假设平衡和试验结果之间存在关系。 如果研究者事先不知道他们将发现什么，如果不确定性原理得到遵守，并且实验疗法的文献相当完整，那么随着时间的推移，我们可以预期，支持实验疗法和支持比较疗法的已发表结果的比例之间没有显著差异。 我们对这个问题进行了早期的调查，发现在由公共资源资助的已发表试验中观察到了这种预期的结果分布，但在由制药公司资助的已发表试验中似乎违反了不确定性原则。 然而，我们不能排除发表偏倚作为文献中阳性结果比例较高的解释。 根据其他研究，未能发表的可能高达51%。 此外，我们无法将我们的数据与临床试验中结局的预期分布进行对比，因为这尚未确定。 因此，不确定性原则与RCT结果之间的真实的关系仍未得到解决。 为了阐明这种关系，我们建议研究一个全面的人口发起的随机对照试验从一个独特的资助者（使用清单的国家癌症研究所申办的试验）。我们的假设将通过以下具体目标来解决：1。 所有在1975年至2001年期间资助的国家癌症研究所（NCI）申办的RCT试验将使用NCI癌症临床试验登记处进行识别。2. e将确定研究者选择用于研究的主要和附加结局。3.我们将回顾这些试验（已发表和未发表），对它们的主要结局和其他结局进行分类，特别是创新或比较治疗是否是首选。4.我们将分析研究者平衡的证据，以及结果与研究质量、比较治疗类型、研究者特征和资金来源的关系。由于违反平衡原则和发表偏倚是RCT研究过程完整性的两个最严重威胁，了解这些因素在RCT研究中的明显程度具有长期意义。 通过理解这些关系，我们将能够为维护高质量的医学临床试验体系做出贡献。 这项建议将回答两个问题“审判为我们做什么？“并评估公众投入如此之多的研究的可靠性。

DESCRIPTION (provided by the applicant): We recently demonstrated that the major threat to research integrity in clinical trials may be due to a violation of the equipoise or "the uncertainty principle," the fundamental principle on which nearly the entire system of human experimentation stands. This principle states that the patient should be enrolled in a randomized controlled trial (RCT) only if there is substantial uncertainty about which of the trial treatments would benefit a patient most. We hypothesize that there is a relationship between equipoise and trials outcomes. If the investigators do not know in advance what they are going to discover, and if the uncertainty principle is observed and the literature on experimental therapies is fairly complete, we would expect, over time, to find no significant difference between the proportion of published results that favor experimental treatments and those that favor comparison treatments. We have performed an earlier investigation on this issue and found that this expected distribution of outcomes was observed among those published trials that were funded by public resources, but that the uncertainty principle appeared to be violated among those published trials funded by pharmaceutical companies. However, we could not exclude publication bias as the explanation for the higher proportion of positive results in the literature. Based on other studies, failure to publish could be as high as 51%. Furthermore, we could not contrast our data with expected distributions of outcomes in Clinical trials, since this has not been determined. Therefore, the real relationship between the uncertainty principle and outcomes of RCTs remains unsettled. To elucidate this relationship, we propose to study a comprehensive population of initiated RCTs from a unique funder (using an inventory of the NCI-sponsored trials). Our hypothesis will be addressed through the following specific aims: 1. All National Cancer Institute (NCI)-sponsored RCTs trials funded in the years 1975 through 2001 will be identified using the NCI registry of clinical trials in cancer. 2. e will identify the primary and additional outcomes selected for study by the investigators. 3. We will review the trials (published and unpublished) to classify their primary and other outcomes, specifically whether the innovative or comparison treatment was preferred. 4. We will perform analyses for evidence of investigators' equipoise, and for the relationship of outcome to study quality, type of comparison treatment, investigator characteristics, and funding source Since violation of the principle of equipoise and publication bias represents two of the most serious threats to the integrity of the research process in RCTs, it is of long-term significance to understand the extent to which these factors are evident in the study of RCTs. By understanding these relationships, we will be in a position to contribute to the preservation of a system of high quality clinical trials in medicine. This proposal will answer both the question "what do trials do for us?" and assess the reliability of the research in which public has invested so much.