Surrogate endpoints: when to use and when not to use? A critical appraisal of current evidences

Abstract Clinical research needs to formulate a question, which must be answered by obeying ethical precepts with well-defined inclusion/exclusion criteria and approval of the study on platforms of ethical appreciation and clinical trial records. In comparing the results or clinically relevant outcomes should be prioritized in the study of techniques, products, inputs, drugs and therapies. However, it is not always possible to use long study drawings, with many participants, and with many costs, then look for study designs with surrogate outcomes, usually a shorter path, with less sample size and considerably lower costs to the research, with shorter intervention time. Considering these outcomes as major challenges in clinical research, the premise of this work was to examine in relevant research platforms, studies on the feasibility of using surrogate endpoints for clinically relevant parameters in dentistry, with a critical evaluation of the advantages, disadvantages, and need for validation of substitute parameters for clinical studies. After a critical analysis of the results, it could be concluded that surrogate endpoints may have an important role in the initial process of developing new drugs, faster, with less sampling, and lower risk of side effects for the patient. Careful use of the surrogate endpoints is advised because, even if validated, they can provide ambiguous evidence and not be extrapolated to other populations, and may lead to bias due to the individual interpretation of each researcher. The use of unplanned surrogate outcomes that arise during the study requires a lot of caution.

摘要 临床研究首先需明确研究问题，且必须遵循伦理准则，采用明确的纳入/排除标准（inclusion/exclusion criteria），并通过伦理评价平台与临床试验备案平台完成研究审批后方可开展。在对技术、产品、耗材、药物及治疗手段开展研究时，应优先关注研究结果或临床相关结局。然而，开展大样本、长周期且高成本的研究往往并非易事，因此研究者会转而采用替代结局的研究设计：这类方案通常周期更短、样本量更小、研究成本显著降低，且干预时长更短。鉴于上述问题均为临床研究面临的主要挑战，本研究旨在通过相关研究平台，调研牙科领域中采用替代终点（surrogate endpoints）替代临床相关参数的可行性，并对替代参数的优势、局限性以及临床研究中的验证必要性开展批判性评估。经对研究结果进行批判性分析后可得出结论：替代终点在新药研发的初始阶段可发挥重要作用，能够缩短研发周期、减少样本量，并降低患者出现不良反应的风险。但需谨慎使用替代终点：即便经过验证，其仍可能提供模棱两可的证据，且无法外推至其他人群；同时，由于不同研究者的解读存在个体差异，可能引入偏倚。对于研究过程中临时出现的非计划替代结局的使用，则需格外谨慎。