Treatment Success and Ethical Principle of Equipoise

评估研究成果，例如估计临床试验中治疗成功的比例，具有重要的伦理、科学和公共政策意义。研究人员、政策制定者、资助机构和公众在了解癌症治疗和预防研究努力的投资回报方面有着共同的利益。这对随机对照试验(RCT)尤其重要，它被广泛认为是评估卫生保健干预效果差异的最可靠方法。这项建议旨在回答最终将发现多少成功的新疗法的问题，作为随机对照试验的测试比例。我们之前的研究使用了美国NCI随机对照试验队列的数据，表明新的治疗方法将成功的时间约为25%到50%。我们假设，治疗成功的这一比例不是偶然的，而是基本的平衡伦理原则的直接结果，该原则一直被倡导为指导随机对照试验行为的核心伦理原则。如果确实如此，那么我们似乎已经描述了可以预测我们当前的随机对照试验系统在产生临床发现方面的效率的基本过程(被称为“临床发现的原理或定律”)。然而，目前还不知道成功率是否相似，或者“均衡假说”是否适用于其他随机对照试验队列。此外，有人声称，在公共资助和行业资助的临床研究中，药物开发的过程是不同的，行业资助的随机对照试验由于对其药物有更好的了解，所以成功率更高。因此，对“均衡假说”的进一步检验应该首先分析由另一家公共机构赞助的新的试验队列，如果结果证实了我们的初步研究，那么我们应该对行业赞助的随机对照试验进行进一步的分析。为了解决我们的假设，我们制定了以下具体目标：目标1：在一个由公共资助的合作小组，即加拿大国家癌症研究所临床试验小组(NCIC-CTG)的队列中，癌症治疗的成功率是多少，这是北美第二大公共赞助试验队列。这项研究的第二个目的是通过考虑可能影响结果的因素来评估结果的稳健性，而不是处理效果之间的真正差异，如发表率(偏差)、方法质量和比较器的选择。如果NCIC-CTG队列的结果证明与我们最初对美国NCI随机对照试验的分析相似，我们将证实“均衡假说”预测随机对照试验的治疗成功。这反过来将为继续分析行业赞助的区域技术合作提供强有力的理由。这项提案的结果将为参与临床研究的各方(患者、研究人员和政策制定者)带来切实的短期和长期好处，他们自然有兴趣了解在临床试验的总体测试中可以发现多少新疗法。此外，AIM#2产生的结果还将增强公众对近年来严重破坏的区域合作研究系统的信任。任何表明临床试验系统完整性可能受到损害的发现都将为即时纠正措施(例如，改进特定的方法缺陷、纠正发表偏差等)提供基础，从而使我们的研究立即得到实际应用。了解“研究回报”以及治疗成功和伦理是如何紧密联系在一起的，对于维持整个临床试验系统的生存至关重要。只有当公众认为这些研究产生了可接受的、可信的、高质量的结果，而不影响研究的完整性时，他们才会继续支持临床试验制度。

Evaluation of research effort, such as estimation of the proportion of treatment successes in clinical trials, has important ethical, scientific, and public policy implications. Researchers, policymakers, funding agencies, and the public share a common interest in knowing the payback on the investments made in the research efforts for the treatment and prevention of cancer. This is particularly important for randomized controlled trials (RCTs), widely considered the most reliable method for assessing differences between effects of health care interventions. This proposal aims to answer the question how many successful new treatments, as a proportion of testing in RCTs, will ultimately be discovered. Our previous research using data from the US NCI cohort of RCTs, indicated that new treatments will be successful about 25% to 50% of time. We have hypothesized that this proportion of treatment success is not accidental, but is a direct consequence of the underlying ethical principle of equipoise, which has been advocated as a central ethical principle guiding the conduct of RCTs. If this indeed is the case, then we would appear to have described the fundamental process (dubbed as the "principle or a law of clinical discovery") which can predict efficiency of our current system of RCTs at generating clinical discoveries. However, it is not known if the success rate would be similar or if the "equipoise hypothesis" will hold true in other cohorts of RCTs. In addition, there have been claims that the process of drug development in publicly and industry-funded clinical research is different, and that industry sponsored RCTs have a better success rate due to better knowledge of their drugs. Therefore, further testing of the "equipoise hypothesis" should be done by first analyzing a new cohort of the trials sponsored by another public agency, and if the results corroborate our preliminary research, we should then pursue further analysis of industry-sponsored RCTs. To address our hypothesis, we have formulated the following specific aims: Aim 1: what is the success rate of cancer treatments in a cohort of publicly funded cooperative group, namely National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG), the second largest cohort of publicly sponsored trials in North America. The second aim of this study is to assess the robustness of the results by accounting for the factors that can affect the results, other than the true differences between the effects of treatments, such as publication rate (bias), methodological quality, and the choice of the comparator. If results from the NCIC-CTG cohort prove similar to our original analysis of the US NCI RCTs, we will corroborate that "equipoise hypothesis" predicts treatment success in RCTs. This in turn will provide a strong rationale to pursue the analysis of industry-sponsored RCTs. The results from this proposal will result in tangible short-term and long-term benefits for all parties involved in clinical research (patients, researchers and policy-makers), who are naturally interested in knowing how many new treatments can be discovered as a proportion of the overall testing in clinical trials. In addition, the results generated from aim #2, will also enhance the public trust in the RCT system, which has been seriously undermined in recent years. Any findings indicating potential compromise in integrity of clinical trial system will provide the basis for instantaneous corrective actions (e.g. improving particular methodological deficiency, correcting for publication bias etc) resulting in the immediate practical application of our research. Understanding the "research payback" and how treatment success and ethics are closely mtertwined is of the crucial importance for maintaining the viability of the entire clinical trial system. The public will continue to support the clinical trial system only if it finds that these studies have produced acceptable rate of successful results that are credible and of high quality without compromised research integrity.