Relationship of Biochemical Response as Surrogate Endpoints with Long-Term Outcomes in Primary Biliary Cholangitis: A Global Systematic Review and Meta-Analysis.
- 1Global Value and Access Gilead Sciences, Inc., Foster City, California, USA.
- 2HEOR Pharmacoevidence, Mohali, India.
Abstract
Background
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease in which long-term clinical outcomes are difficult to assess within conventional trial durations. Alkaline phosphatase (ALP) and bilirubin are established biochemical endpoints in regulatory and clinical practice, and their relationship with long-term clinical outcomes has been demonstrated through a robust literature of analyses across different datasets. However, the magnitude and consistency of their association with long-term clinical outcomes have not been systematically quantified through meta-analysis.Objective
This systematic literature review and meta-analysis aimed to identify, evaluate, and summarize evidence on the correlation between surrogate biochemical endpoints and long-term clinical outcomes in patients with PBC.Methods
A comprehensive search of key biomedical databases and reporting was conducted, in accordance with Cochrane, NICE and PRISMA guidelines. Meta-analysis was performed using Stata 19.5 SE software, with the DerSimonian and Laird (DL) random-effects model employed in the base-case, inverse-variance fixed-effect and DL + Hartung-Knapp-Sidik-Jonkman random effects model were used in sensitivity analyses. Other sensitivity analyses were performed based on study/follow-up duration, study quality, publication type, and removal of heterogeneous studies.Results
Overall, 129 studies were included in the systematic literature review, among which 89 studies met criteria for meta-analysis. Failure to achieve ALP normalization was associated with significantly increased risks of composite clinical outcomes (HR; 95% CI: 1.46; 1.26-1.69), liver-related events (1.82; 1.41-2.34), and overall death and/or liver transplantation (1.52; 1.30-1.79). Similar findings were reported for other ALP response definitions. Nonresponse to composite criteria was also associated with significantly worse long-term outcomes. Sensitivity analyses yielded directionally consistent results.Discussion
To our knowledge, this research represents the first comprehensive meta-analytic evaluation integrating multiple surrogate biochemical endpoints with a broad spectrum of long-term clinical outcomes in PBC across a global study population. Associations were directionally consistent across ALP-, bilirubin-, and composite-based definitions and across all analyses.Conclusion
This meta-analysis provides robust evidence that ALP normalization, ALP-based response criteria, and composite biochemical response measures (comprising ALP and total bilirubin), were consistently associated with long-term clinical outcomes in PBC and may inform HTA, reimbursement, payer decision-making, and economic evaluation when mature long-term outcome data are unavailable.
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BibTeX
@article{makhija2026relationship,
title = {{Relationship of Biochemical Response as Surrogate Endpoints with Long-Term Outcomes in Primary Biliary Cholangitis: A Global Systematic Review and Meta-Analysis.}},
author = {Dilip Makhija and Marvin Rock and Chong H Kim and Ryan Thaliffdeen and Pankaj Rai and Barinder Singh},
journal = {Journal of health economics and outcomes research},
year = {2026},
month = oct,
doi = {10.36469/001c.170737},
url = {https://europepmc.org/article/MED/42968947},
note = {CC BY},
}
RIS
TY - JOUR
TI - Relationship of Biochemical Response as Surrogate Endpoints with Long-Term Outcomes in Primary Biliary Cholangitis: A Global Systematic Review and Meta-Analysis.
AU - Dilip Makhija
AU - Marvin Rock
AU - Chong H Kim
AU - Ryan Thaliffdeen
AU - Pankaj Rai
AU - Barinder Singh
PY - 2026
DA - 2026/10/30
JO - Journal of health economics and outcomes research
DO - 10.36469/001c.170737
UR - https://europepmc.org/article/MED/42968947
AB - Background Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease in which long-term clinical outcomes are difficult to assess within conventional trial durations. Alkaline phosphatase (ALP) and bilirubin are established biochemical endpoints in regulatory and clinical practice, and their relationship with long-term clinical outcomes has been demonstrated through a robust literature of analyses across different datasets. However, the magnitude and consistency of their association with long-term clinical outcomes have not been systematically quantified through meta-analysis.Objective This systematic literature review and meta-analysis aimed to identify, evaluate, and summarize evidence on the correlation between surrogate biochemical endpoints and long-term clinical outcomes in patients with PBC.Methods A comprehensive search of key biomedical databases and reporting was conducted, in accordance with Cochrane, NICE and PRISMA guidelines. Meta-analysis was performed using Stata 19.5 SE software, with the DerSimonian and Laird (DL) random-effects model employed in the base-case, inverse-variance fixed-effect and DL + Hartung-Knapp-Sidik-Jonkman random effects model were used in sensitivity analyses. Other sensitivity analyses were performed based on study/follow-up duration, study quality, publication type, and removal of heterogeneous studies.Results Overall, 129 studies were included in the systematic literature review, among which 89 studies met criteria for meta-analysis. Failure to achieve ALP normalization was associated with significantly increased risks of composite clinical outcomes (HR; 95% CI: 1.46; 1.26-1.69), liver-related events (1.82; 1.41-2.34), and overall death and/or liver transplantation (1.52; 1.30-1.79). Similar findings were reported for other ALP response definitions. Nonresponse to composite criteria was also associated with significantly worse long-term outcomes. Sensitivity analyses yielded directionally consistent results.Discussion To our knowledge, this research represents the first comprehensive meta-analytic evaluation integrating multiple surrogate biochemical endpoints with a broad spectrum of long-term clinical outcomes in PBC across a global study population. Associations were directionally consistent across ALP-, bilirubin-, and composite-based definitions and across all analyses.Conclusion This meta-analysis provides robust evidence that ALP normalization, ALP-based response criteria, and composite biochemical response measures (comprising ALP and total bilirubin), were consistently associated with long-term clinical outcomes in PBC and may inform HTA, reimbursement, payer decision-making, and economic evaluation when mature long-term outcome data are unavailable.
SN - 2326-697X
SN - 2327-2236
ER -