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。该原则指出，只有在不确定哪种试验治疗对患者最有利的情况下，患者才应该参加随机对照试验（RCT）。我们假设在平衡和试验结果之间存在一种关系。如果研究者事先不知道他们将要发现什么，如果不确定性原则被遵守，并且实验疗法的文献是相当完整的，我们将期望，随着时间的推移，发现赞成实验疗法和赞成比较疗法的已发表结果的比例之间没有显著差异。我们对这一问题进行了较早的调查，发现在那些由公共资源资助的已发表试验中观察到这种预期的结果分布，但在那些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，我们不能排除文献中阳性结果比例较高的原因是发表偏倚。根据其他研究，未能发表的比例可能高达51%。此外，我们无法将我们的数据与临床试验结果的预期分布进行对比，因为这尚未确定。因此，不确定性原则与随机对照试验结果之间的真正关系仍未解决。

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.