TY - JOUR
T1 - Innovations in Pediatric Therapeutics Development
T2 - Principles for the Use of Bridging Biomarkers in Pediatric Extrapolation
AU - Fleming, Thomas R.
AU - Garnett, Christine E.
AU - Conklin, Laurie S.
AU - Corriol-Rohou, Solange
AU - Hariharan, Sudharshan
AU - Hsu, Daphne
AU - Mueller-Velten, Guenther
AU - Mulugeta, Yeruk
AU - Portman, Ronald
AU - Rothmann, Mark D.
AU - Stockbridge, Norman L.
AU - Wandel, Simon
AU - Zhang, Jialu
AU - Yao, Lynne
N1 - Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Heart failure
KW - Pediatric extrapolation
KW - Pulmonary arterial hypertension
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U2 - 10.1007/s43441-022-00445-6
DO - 10.1007/s43441-022-00445-6
M3 - Article
C2 - 36057747
AN - SCOPUS:85137531557
SN - 2168-4790
VL - 57
SP - 109
EP - 120
JO - Therapeutic Innovation and Regulatory Science
JF - Therapeutic Innovation and Regulatory Science
IS - 1
ER -