Quantifying the feasibility of shortening clinical trial duration using surrogate markers

The potential benefit of using a surrogate marker in place of a long‐term primary outcome is very attractive in terms of the impact on study length and cost. Many available methods for quantifying the effectiveness of a surrogate endpoint either rely on strict parametric modeling assumptions or requ...

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Bibliographic Details
Published in:Statistics in medicine 2021-12, Vol.40 (28), p.6321-6343
Main Authors: Wang, Xuan, Cai, Tianxi, Tian, Lu, Bourgeois, Florence, Parast, Layla
Format: Article
Language:English
Subjects:
Biomarkers
censored data
Clinical Trials as Topic
Computer Simulation
Diabetes
Feasibility Studies
Humans
nonparametric estimation
Nonparametric statistics
proportion of treatment effect explained by the surrogate
surrogate marker
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Summary:The potential benefit of using a surrogate marker in place of a long‐term primary outcome is very attractive in terms of the impact on study length and cost. Many available methods for quantifying the effectiveness of a surrogate endpoint either rely on strict parametric modeling assumptions or require that the primary outcome and surrogate marker are fully observed that is, not subject to censoring. Moreover, available methods for quantifying surrogacy typically provide a proportion of treatment effect explained (PTE) measure and do not directly address the important questions of whether and how the trial can be ended earlier using the surrogate marker. In this article, we specifically address these important questions by proposing a PTE measure to quantify the feasibility of ending trials early based on endpoint information collected at an earlier landmark point t0 in a time‐to‐event outcome setting. We provide a framework for deriving an optimally predicted outcome for individual patients at t0 based on a combination of surrogate marker and event time information in the presence of censoring. We propose a non‐parametric estimator for the PTE measure and derive the asymptotic properties of our estimators. Finite sample performance of our estimators are illustrated via extensive simulation studies and a real data application examining the potential of hemoglobin A1c and fasting plasma glucose to predict treatment effects on long term diabetes risk based on the Diabetes Prevention Program study.
ISSN:0277-6715
1097-0258
1097-0258
DOI:10.1002/sim.9185