Treatment Success and Ethical Principle of Equipoise

对研究成果的评估，如对临床试验中治疗成功比例的估计，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、资助机构和公众都有一个共同的兴趣，那就是了解为治疗和预防癌症而进行的研究投资的回报。这对于随机对照试验（RCTs）尤其重要，随机对照试验被广泛认为是评估卫生保健干预措施效果差异的最可靠方法。该提案旨在回答这样一个问题：作为随机对照试验的一部分，最终将发现多少成功的新疗法。我们之前的研究使用了来自美国NCI随机对照试验队列的数据，表明新疗法的成功率约为25%至50%。我们假设治疗成功的比例不是偶然的，而是潜在的平衡伦理原则的直接结果，这一原则一直被提倡作为指导随机对照试验行为的核心伦理原则。如果情况确实如此，那么我们似乎已经描述了基本过程（被称为“临床发现的原则或法则”），它可以预测我们目前的随机对照试验系统在产生临床发现方面的效率。然而，目前尚不清楚成功率是否相似，或者“均衡假设”是否在其他随机对照试验中成立。此外，有人声称，公共和行业资助的临床研究的药物开发过程是不同的，行业资助的随机对照试验有更好的成功率，因为他们对药物有更好的了解。因此，对“均衡假设”的进一步检验应该首先通过分析另一个公共机构赞助的新队列试验来完成，如果结果证实了我们的初步研究，那么我们应该进一步分析行业赞助的随机对照试验。为了解决我们的假设，我们制定了以下具体目标：目标1：在一个公共资助的合作组队列中，即加拿大国家癌症研究所临床试验组（NCIC-CTG），北美第二大公共资助试验队列，癌症治疗的成功率是多少？本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，而不是考虑治疗效果之间的真正差异，如发表率（偏倚）、方法学质量和比较器的选择。如果NCI - ctg队列的结果与我们对美国NCI随机对照试验的原始分析相似，我们将证实“平衡假设”预测了随机对照试验的治疗成功。这反过来将为进行行业赞助的随机对照试验的分析提供强有力的依据。这项提案的结果将为临床研究的所有各方（患者、研究人员和政策制定者）带来切实的短期和长期利益，他们自然想知道在临床试验的总体测试中可以发现多少新的治疗方法。此外，目标2产生的结果也将增强公众对RCT系统的信任，这种信任近年来受到严重破坏。任何表明临床试验系统完整性存在潜在危害的发现都将为即时纠正措施（例如改进特定方法缺陷，纠正发表偏倚等）提供基础，从而立即将我们的研究应用于实际。了解“研究回报”以及治疗成功与伦理是如何紧密交织在一起的，对于维持整个临床试验系统的可行性至关重要。只有当公众发现这些研究产生了可接受的、可信的、高质量的、不损害研究完整性的成功结果时，他们才会继续支持临床试验系统。

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.