Using Outcomes Analyses to Inform Implementation of NINDS Clinical Trials

描述(申请人提供)：随机对照试验(RCT)的结果缓慢地扩散到临床实践中--从试验完成到广泛采用一种新疗法的平均时间接近20年。这些延误导致神经疾病患者的治疗不太理想。鉴于这些延迟和NINDS临床试验结果的巨大社会价值，NINDS认识到有必要通过促进将试验结果转化为常规护理的研究(T2翻译研究)来加快实施。该应用程序寻求通过个性化临床试验结果并为临床医生和政策制定者解决翻译障碍来优化NINDS试验的翻译。使用转化性研究方法，我们可以通过估计个别患者的治疗效益，从一刀切的循证医学转向个性化医学。其他翻译方法可以评估和解决阻碍翻译的利益相关者关注的问题。因为临床医生通常对试验结果持怀疑态度，改变做法需要让他们相信，一种治疗不仅在随机对照试验中有效，或者在学术医学中心有效，而且对他们的患者有效。同样，如果政策制定者和支付者能够确信一种新的治疗是一种好的价值(例如，有利的成本效益比)，他们可以利用他们对医疗保健提供系统的相当大的影响力来促进翻译。具体地说，我们将使用翻译研究方法来解决提高试译水平的三个重要问题：1.使用多变量结果预测来估计个人水平的结果；2.使用模拟分析来估计现实世界环境对结果的影响；以及3.成本效益分析。这些分析的结果可以直接或通过使用网站和移动应用程序等工具来影响临床医生和政策制定者。这项提议有两个关键目标。首先，我们将通过解决颈动脉内膜切除术与支架植入(CREST)试验中与翻译相关的基本问题，将翻译研究方法应用于临床试验。其次，我们将开发一个模型，在神经病学紧急治疗试验(NETT)网络中同时执行类似的翻译分析。这些目标将通过3个具体目标来实现：1.使用改进的多变量结果预测方法，评估CREST试验中颈动脉内膜剥脱术(CEA)与颈动脉支架植入(CAS)的预期净效益。2.使用模拟分析评估个性化决策和现实世界环境(例如，不同的并发症发生率)对现实世界患者的CAS与CEA的净收益的影响。3.通过评估新启动和最近完成的NETT试验中的过程实施模型，评估在NETT试验中执行并行翻译和成本分析的可行性。作为一名血管神经学家，伯克博士拥有独特的背景，并通过备受推崇的罗伯特·伍德·约翰逊临床学者计划接受过翻译研究方法论方面的培训。在这项提案中，Burke博士将在临床试验、多变量结果预测、模拟分析和成本分析方面发展更多的专业知识，成为神经学翻译研究领域的领导者和独立资助的调查者，致力于开发新一代NETT试验，以更有效地为现实世界的临床实践提供信息，并改善患者的结果。这项提议充分利用了密歇根大学独特的环境优势。最重要的是，Burke博士将得到杰出的多学科指导团队的支持，其中包括NETT临床协调中心(CCC)首席研究员和神经系统疾病紧急治疗研究负责人William Barsan博士，内科教授和翻译研究先驱Rodney Hayward博士，以及神经学翻译研究领导者Lewis Morgenstein博士。这三位导师在指导初级教员和将初级教员过渡到独立教师方面都有出色的记录。此外，Burke博士将有机会通过NETT参加一次独特的亲身临床试验，以获得临床试验设计、管理和实施方面的经验。最后，密歇根大学最近建立了美国最大的学术转化研究中心(卫生政策和创新研究所)，该中心将支持先进的统计 这项建议所需的方法。

DESCRIPTION (provided by applicant): Randomized controlled trial (RCT) results diffuse into clinical practice slowly - the average time from trial completion to widespread adoption of a new treatment is nearly 20 years. These delays result in suboptimal treatment for patients with neurological diseases. In light of these delays and the enormous societal value of NINDS clinical trials findings, NINDS has recognized the need to accelerate implementation by promoting research to translate trial findings into routine care (T2 translational research). This application seeks to optimize translation of NINDS trials by personalizing clinical trial results ad addressing barriers to translation for clinicians and policy-makers. Using translational research methods, we can move from one-size-fits-all evidence-based medicine towards personalized medicine by estimating treatment benefit for individual patients. Other translational methods can evaluate and address stakeholder concerns that hinder translation. Because clinicians are often skeptical of trial results, changing practice requires convincing them not only that a treatment works in an RCT or that it works in academic medical centers, but that it will work for their patients. Similarly, if policy-makers and payers can be convinced that a new treatment is a good value (e.g., a favorable cost-benefit ratio), they can use their considerable influence on the healthcare delivery system to facilitate translation. Specifically, we will use translational research methods to address three important issues essential to improving trial translation: 1. estimating individual-level outcomes using multivariable outcome prediction 2. Estimating the impact of real world circumstances on outcomes using simulation analyses and 3. Cost effectiveness analysis. Results from these analyses can influence clinicians and policy-makers directly or through the use of tools, such as websites and mobile applications. This proposal has two key objectives. First, we will adapt translational research methods to clinical trials by addressing essential translation-relevant questions for the Carotid Revascularization Endarterectomy versus Stenting (CREST) trial. Second, we will develop a model to concurrently perform similar translational analyses in the Neurology Emergency Treatment Trials (NETT) network. These objectives will be addressed through 3 specific aims: 1. to estimate the expected net benefit of carotid endarterectomy (CEA) vs. carotid artery stenting (CAS) for individual patients in the CREST trial using refined multivariable outcome prediction methods. 2. To estimate the impact of personalized decision-making and real world circumstances (e.g., differing complication rates) on the net benefit of CAS vs. CEA for real world patients using simulation analyses. 3. To assess the feasibility of performing concurrent translational and cost analyses in NETT trials by evaluating a process implementation model in newly initiated and recently completed NETT trials. Dr. Burke has a unique background as a vascular neurologist with training in Translational research methodology through the highly regarded Robert Wood Johnson Clinical Scholars Program. In this proposal, Dr. Burke will develop the additional expertise in clinical trials, multivariable outcome prediction, simulation analyses and cost analyses to become a leader and independently-funded investigator in neurological translational research working to develop a new generation of NETT trials better designed to effectively inform real world clinical practice and improve patient outcomes. This proposal capitalizes on unique environmental strengths at the University of Michigan. Most importantly, Dr. Burke will be supported by an outstanding multi- disciplinary mentorship team including Dr. William Barsan the NETT Clinical Coordinating Center (CCC) principal investigator and a research leader in the emergency treatment of neurological diseases, Dr. Rodney Hayward a Professor of Internal Medicine and a pioneer in translational research and Dr. Lewis Morgenstern, a leader in neurological translational research. All three mentors have excellent track records in mentoring junior faculty and transitioning junior faculty to independence. In addition, Dr. Burke will have te opportunity to participate in a unique hands-on clinical trials immersion through the NETT to gain experience in clinical trial design, management and implementation. Finally, the University of Michigan has recently built the largest academic Translational Research center in the United States (the Institute for Health Policy and Innovation) which will support the advanced statistical methods required for this proposal.