Treatment Success and Ethical Principle of Equipoise

对研究成果的评估，如临床试验中治疗成功率的估计，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共同的兴趣，希望了解在癌症治疗和预防研究工作中所做投资的回报。这对于随机对照试验（RCT）尤其重要，RCT被广泛认为是评估医疗保健干预措施效果差异的最可靠方法。这项提案旨在回答这样一个问题：最终将发现多少成功的新疗法，作为RCT测试的一部分。我们之前的研究使用了美国NCI随机对照试验队列的数据，表明新治疗方法的成功率约为25%至50%。我们假设，这一比例的治疗成功不是偶然的，而是平衡的基本伦理原则的直接后果，这已被提倡为指导RCT的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”），可以预测我们目前的RCT系统在产生临床发现方面的效率。然而，尚不清楚成功率是否相似，或者“平衡假设”是否在其他RCT队列中成立。此外，有人声称，公共和行业资助的临床研究中的药物开发过程是不同的，行业赞助的RCT由于对其药物的更好了解而具有更好的成功率。因此，对“均衡假设”的进一步检验应该首先分析另一个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，我们应该进一步分析行业赞助的RCT。为了解决我们的假设，我们制定了以下具体目标：目标1：在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），北美第二大公共赞助试验队列中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（治疗效果之间的真实差异除外），如发表率（偏倚）、方法学质量和比较药物的选择，评估结果的稳健性。如果NCIC-CTG队列的结果证明与我们对美国NCI RCT的原始分析相似，我们将证实“平衡假设”预测RCT中的治疗成功。这反过来将为继续分析行业申办的RCT提供强有力的依据。该提案的结果将为参与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，他们自然有兴趣了解在临床试验的总体测试中，有多少新的治疗方法可以被发现。此外，目标2所产生的结果也将提高公众对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可能受损的发现将为立即采取纠正措施（例如，改善特定的方法学缺陷，纠正发表偏倚等）提供依据，从而立即将我们的研究付诸实际应用。了解“研究回报”以及治疗成功和伦理如何密切相关，对于维持整个临床试验系统的可行性至关重要。只有当公众认为这些研究产生了可接受的成功率，并且是可信的和高质量的，而又不损害研究的完整性时，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.