VALIDATION OF SURROGATE ENDPOINTS IN ADVANCED SOLID TUMORS: SYSTEMATIC REVIEW OF STATISTICAL METHODS, RESULTS, AND IMPLICATIONS FOR POLICY MAKERS
VALIDATION OF SURROGATE ENDPOINTS IN ADVANCED SOLID TUMORS: SYSTEMATIC REVIEW OF STATISTICAL METHODS, RESULTS, AND IMPLICATIONS FOR POLICY MAKERS
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DOI：
10.1017/s0266462314000300
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发表时间：
2014-07-01
影响因子：
3.2
通讯作者：
Taylor, Rod S.
中科院分区：
文献类型：
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作者：
Ciani, Oriana;Cantrell, Anna;Taylor, Rod S.
目的：新疗法的许可和覆盖决定应依赖于患者相关终点的证据，如总存活率(OS)。然而，来自代理终点的证据也可能是有用的，因为它不仅可以加快监管部门对新疗法的批准，还可以为覆盖决定提供信息。因此，适当地验证候选代理终结点是至关重要的。然而，对于这种验证的统计方法以及由此得出的证据应该如何被政策制定者应用，还没有达成共识。方法：我们回顾了当前在各种晚期肿瘤环境下基于荟萃分析的替代终点验证的统计方法。我们使用三个现有的验证框架：Elston and Taylor‘s框架、德国医疗质量与效率研究所(IQWiG)框架和Biomarker-代理评估模式(BSES3)，评估了两种代孕方法(无进展生存[PFS]和进展时间[TTP])的适宜性。这两个代孕药与OS之间的关联强度普遍较低。可获得的证据水平(观察水平与治疗水平)因癌症类型、评估工具的不同而有很大不同，甚至在一种特定的癌症类型中也不总是一致的。结论：并不是在所有实体肿瘤中，PFS或TTP与OS的治疗水平之间的关联已被调查。根据IQWiG的框架，只有PFS在接受细胞毒剂治疗的转移性结直肠癌和卵巢癌中获得了可接受的代孕证据。我们的研究强调了替代终点验证的挑战，以及就评估框架的发展建立共识的重要性。
Objectives: Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers.Methods: We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3).Results: A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type.Conclusions: Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.