Exploring the Relationship Between Surrogate Endpoints and Clinical Outcomes in Primary Biliary Cholangitis: A Systematic Literature Review and Meta-Analysis
Author(s)
Dilip Makhija, MS1, Marvin Rock, DrPH, MPH1, Chong H Kim, MPH, MS, PhD1, Mirko von Hein, M.Sc.2, Ryan Thaliffdeen, BS, MS, PharmD1, Oskar Eklund, MSc3, Pankaj Rai, MS4, Howard Thom, BA, MSc, PhD5, Gianluca Baio, PhD6, Barinder Singh, RPh4.
1Gilead Sciences, Inc., Foster City, CA, USA, 2Gilead Sciences, London, United Kingdom, 3Gilead Sciences AB, Solna, Sweden, 4Pharmacoevidence, Mohali, India, 5Clifton Insight, Bristol, United Kingdom, 6University College London, London, United Kingdom.
1Gilead Sciences, Inc., Foster City, CA, USA, 2Gilead Sciences, London, United Kingdom, 3Gilead Sciences AB, Solna, Sweden, 4Pharmacoevidence, Mohali, India, 5Clifton Insight, Bristol, United Kingdom, 6University College London, London, United Kingdom.
Presentation Documents
OBJECTIVES: Primary biliary cholangitis (PBC) is a rare, chronic autoimmune liver disease characterized by slow progression, making it challenging to assess long-term clinical outcomes, such as liver transplantation (LT) and death. Cholestatic marker alkaline phosphatase (ALP) has been used to assess treatment effect in clinical trials and guide therapeutic decisions in routine practice. A systematic literature review (SLR) was conducted to identify studies evaluating the association between ALP-based surrogate endpoints and long-term clinical outcomes in PBC.
METHODS: The key biomedical databases (Embase®, PubMed®, and Cochrane) were searched up to September 2024. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The meta-analysis was performed using Stata 17 software, employing the DL+HKSJ method, which combines the DerSimonian and Laird random-effects model with the Hartung-Knapp-Sidik-Jonkman adjustment for improved confidence interval (CI) accuracy.
RESULTS: Overall, 38 studies were included, reporting an association between ALP response or normalization and clinical outcomes. Across these studies, death or liver transplantation (LT) were the most reported hard clinical endpoints (n=15). In most of the studies, patients were treated with UDCA alone or in combination with fibrates. The most commonly used ALP response criteria were Barcelona (ALP reduction ≥40%; n=18) and Toronto I (ALP ≤1.67 × ULN; n=18), followed by ALP normalization (ALP ≤1 × ULN; n=7) and Toronto II (ALP ≤1.76 X ULN; n=3). Patients who did not meet the ALP response or normalization criteria showed a significantly higher risk of LT or death compared to responders (Hazard ratio (HR): 2.18 95% CI [1.76-2.70]).
CONCLUSIONS: The study findings emphasize the prognostic value of ALP reduction and normalization in guiding clinical decisions and monitoring treatment efficacy. These results support the integration of biomarker-based strategies to improve PBC management, potentially reducing the clinical and economic burden on patients.
METHODS: The key biomedical databases (Embase®, PubMed®, and Cochrane) were searched up to September 2024. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The meta-analysis was performed using Stata 17 software, employing the DL+HKSJ method, which combines the DerSimonian and Laird random-effects model with the Hartung-Knapp-Sidik-Jonkman adjustment for improved confidence interval (CI) accuracy.
RESULTS: Overall, 38 studies were included, reporting an association between ALP response or normalization and clinical outcomes. Across these studies, death or liver transplantation (LT) were the most reported hard clinical endpoints (n=15). In most of the studies, patients were treated with UDCA alone or in combination with fibrates. The most commonly used ALP response criteria were Barcelona (ALP reduction ≥40%; n=18) and Toronto I (ALP ≤1.67 × ULN; n=18), followed by ALP normalization (ALP ≤1 × ULN; n=7) and Toronto II (ALP ≤1.76 X ULN; n=3). Patients who did not meet the ALP response or normalization criteria showed a significantly higher risk of LT or death compared to responders (Hazard ratio (HR): 2.18 95% CI [1.76-2.70]).
CONCLUSIONS: The study findings emphasize the prognostic value of ALP reduction and normalization in guiding clinical decisions and monitoring treatment efficacy. These results support the integration of biomarker-based strategies to improve PBC management, potentially reducing the clinical and economic burden on patients.
Conference/Value in Health Info
2025-05, ISPOR 2025, Montréal, Quebec, CA
Value in Health, Volume 28, Issue S1
Code
CO170
Topic
Clinical Outcomes
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
SDC: Rare & Orphan Diseases, SDC: Systemic Disorders/Conditions (Anesthesia, Auto-Immune Disorders (n.e.c.), Hematological Disorders (non-oncologic), Pain)