Relationship of Biochemical Response as Surrogate Endpoints with Long-Term Outcomes in Primary Biliary Cholangitis: A Global Systematic Review and Meta-Analysis

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.

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.

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.

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.

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.

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.