Department of Biostatistics, University of Washington, Seattle, WA, USA.
Division of Cardiology and Nephrology, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Ther Innov Regul Sci. 2023 Jan;57(1):109-120. doi: 10.1007/s43441-022-00445-6. Epub 2022 Sep 3.
Even with recent substantive improvements in health care in pediatric populations, considerable need remains for additional safe and effective interventions for the prevention and treatment of diseases in children. The approval of prescription drugs and biological products for use in pediatric settings, as in adults, requires demonstration of substantial evidence of effectiveness and favorable benefit-to-risk. For diseases primarily affecting children, such evidence predominantly would be obtained in the pediatric setting. However, for conditions affecting both adults and children, pediatric extrapolation uses scientific evidence in adults to enable more efficiently obtaining a reliable evaluation of an intervention's effects in pediatric populations. Bridging biomarkers potentially have an integral role in pediatric extrapolation. In a setting where an intervention reliably has been established to be safe and effective in adults, and where there is substantive evidence that disease processes in pediatric and adult settings are biologically similar, a 'bridging biomarker' should satisfy three additional criteria: effects on the bridging biomarker should capture effects on the principal causal pathway through which the disease process meaningfully influences 'feels, functions, survives' measures; secondly, the experimental intervention should not have important unintended effects on 'feels, functions, survives' measures not captured by the bridging biomarker; and thirdly, in statistical analyses in adults, the intervention's net effect on 'feels, functions, survives' measures should be consistent with what would be predicted by its level of effect on the bridging biomarker. A validated bridging biomarker has considerable potential utility, since an intervention's efficacy could be extrapolated from adult to pediatric populations if evidence in children establishes the intervention not only to be safe but also to have substantive effects on that bridging biomarker. Proper use of bridging biomarkers could increase availability of reliably evaluated therapies approved for use in pediatric settings, enabling children and their caregivers to make informed choices about health care.
即使在儿科人群的医疗保健方面最近取得了实质性的进展，但仍需要更多安全有效的干预措施来预防和治疗儿童疾病。与成人一样，批准用于儿科环境的处方药和生物制品需要证明其具有实质性的有效性和有利的风险效益。对于主要影响儿童的疾病，此类证据主要将在儿科环境中获得。然而，对于同时影响成人和儿童的疾病，儿科外推使用成人中的科学证据，使人们能够更有效地对干预措施在儿科人群中的效果进行可靠评估。桥接生物标志物在儿科外推中可能具有重要作用。在一种情况下，干预措施在成人中已被可靠地证明是安全有效的，并且有实质性证据表明儿科和成人环境中的疾病过程在生物学上是相似的，那么“桥接生物标志物”应满足以下三个额外标准：对桥接生物标志物的影响应捕获疾病过程通过主要因果途径对“感觉、功能、生存”测量的影响；其次，实验干预措施不应对桥接生物标志物未捕获的“感觉、功能、生存”测量指标产生重要的意外影响；第三，在成人的统计分析中，干预措施对“感觉、功能、生存”测量指标的净效应应与其对桥接生物标志物的效应水平一致。经过验证的桥接生物标志物具有相当大的潜在效用，因为如果在儿童中建立的证据不仅表明干预措施安全，而且对该桥接生物标志物具有实质性影响，那么可以从成人外推干预措施的疗效到儿科人群。正确使用桥接生物标志物可以增加在儿科环境中批准使用的可靠评估治疗方法的可用性，使儿童及其护理人员能够就医疗保健做出明智的选择。
