A framework for multi-indication evidence synthesis in oncology Health Technology Assessment

越来越多的药物被用于治疗不同类型的癌症。这些药物有共同的作用机制，如阻断癌症血管生长(贝伐单抗等抗血管生成药物)。这些药物通常首先得到监管当局的许可，用于特定的适应症(针对特定治疗线中的特定癌症组织学)，随着时间的推移，它们的许可证将延长，以包括更多的适应症。例如，贝伐单抗目前被监管机构批准用于11种适应症。在特定适应症的监管许可证颁发后，卫生系统将评估该药物的临床和经济价值，以确定该适应症的患者是否可以获得(资助)该药物。这被称为卫生技术评估(HTA)。支持HTA的证据通常包括一项特定适应症的研究，该研究可以基于中间(替代)结果，如无进展生存，而不是HTA机构所要求的与患者相关的最终终点(例如总存活率)。对单一适应症的关注意味着每一次评估都受到最终终点高度证据不确定性的影响，即使有关于药物的其他适应症的大量证据也是如此。我们建议探索是否可以通过查看迹象以及内部迹象来更好地利用证据。这种分析将在不同适应症之间共享信息，减少现有适应症的决策不确定性，并对未来适应症的药物价值提供更现实的预测。因此，这个项目的总体目标是开发一个多适应症证据合成的框架，以支持肿瘤学HTA。该框架将概述确定、进行和解释多适应症证据合成所需的判断和分析，并将纳入一套工具。三个相辅相成的方法学工作包将支持框架的发展：WP1：提出和总结本工作包中的证据，我们将确定贝伐单抗在其11个适应症中的相对有效性证据，这是将在本工作方案中用作范例的真实案例研究。为了支持多适应症分析，重要的是对证据基础进行适当的总结，以供临床和政策决策者考虑。因此，我们将把现有的证据映射方法扩展到多适应症肿瘤学环境(跨适应症，具有多个结果，并显示证据的不成熟程度)。WP2：多指征证据合成方法在本工作包中，我们将开发肿瘤学中的多指征证据合成方法。我们将考虑在单个端点上的指示上共享信息的模型，或者，在代理关系上的指示上共享信息的模型。我们还将制定方法，明确这些方法施加的适应症的共享程度，确保决策者和临床专家可以明确考虑潜在假设的适当性。WP3：支持政策框架的额外工作我们将进行一项模拟研究，从贝伐单抗案例研究总结到更广泛的多适应症药物集，并支持框架关于何时多适应症分析可能值得或可能不值得的建议和指导原则。我们还将开发正式启发临床专家判断的方法，以支持多适应症分析。最后，我们将通过使用贝伐单抗案例研究评估整合多适应症证据合成对成本效益的影响，展示更充分地使用多适应症证据如何有助于HTA决策。

An increasing number of drugs are used to treat different types of cancer. These present a common mechanism of action, such as blocking cancer blood vessel growth (anti-angiogenics such as bevacizumab). These drugs are typically first licensed by regulatory authorities for use in a specific indication (for a particular cancer histology in a particular line of treatment), and over time their licences are extended to include additional indications. Bevacizumab, for example, is currently approved by regulators for use in 11 indications.Closely after the regulatory license is awarded for a particular indication, the drug is appraised (for clinical and economic value) by health systems to determine whether it is made available (funded) to patients in that indication. This is called Health Technology Assessment (HTA). The evidence supporting HTA typically comprises of an indication-specific study that can be powered on intermediate (surrogate) outcomes, such as progression-free survival, rather than the final patient-relevant endpoints required by HTA agencies (e.g. overall survival). The focus on single indications means that every appraisal is subject to a high level of evidential uncertainty on final endpoints, even where considerable evidence on the drug exists for other indications. We propose exploring whether better use of evidence can be made by looking across, as well as within, indications. Such analyses would share information across indications, reducing decision uncertainty across the existing indications and providing more realistic predictions of the value of the drug in future indications. The overall aim of this project is, therefore, to develop a framework for multi-indication evidence synthesis to support oncology HTA. The framework will outline the judgements and analyses required to specify, conduct, and interpret the synthesis of multi-indication evidence, and will incorporate a package of tools.Three complementary work packages of methodological work will support the development of the framework:WP1: Presenting and summarising evidence In this work package, we will identify the relative effectiveness evidence for bevacizumab across its 11 indications, the real case study that will be used as an exemplar in this programme of work. To support multi-indication analyses, it is important that the evidence base is summarised appropriately for consideration by clinical and policy decision makers. Therefore, we will extend existing methods for the mapping of evidence to the multi-indication oncology setting (across indications, with multiple outcomes, and displaying the level of immaturity of evidence). WP2: Methods for multi-indication evidence synthesisIn this work package, we will develop methods for multi-indication evidence synthesis in oncology. We will consider models for sharing of information across indications on a single endpoint and, alternatively, for sharing of information across indications on surrogate relationships. We will also develop methods for making explicit the level of sharing across indications imposed by the methods, ensuring that the appropriateness of the underlying assumptions can be explicitly considered by decision makers and clinical experts. WP3: Additional work to support a policy framework We will perform a simulation study to generalise from the bevacizumab case study to a broader set of multi-indication drugs and support the framework's recommendations and guiding principles relating to when multi-indication analyses may, or may not, be worthwhile. We will also develop methods for the formal elicitation of the judgment of clinical experts to support multi-indication analyses. Finally, we will demonstrate how the fuller use of multi-indication evidence can contribute to HTA decisions, by evaluating the impact on cost-effectiveness of integrating multi-indication evidence synthesis using the bevacizumab case study.