title: A Bayesian hierarchical surrogate outcome model for multiple sclerosis.
abstract: The development of novel therapies in multiple sclerosis (MS) is one area where a range of surrogate outcomes are used in various stages of clinical research. While the aim of treatments in MS is to prevent disability, a clinical trial for evaluating a drugs effect on disability progression would require a large sample of patients with many years of follow-up. The early stage of MS is characterized by relapses. To reduce study size and duration, clinical relapses are accepted as primary endpoints in phase III trials. For phase II studies, the primary outcomes are typically lesion counts based on magnetic resonance imaging (MRI), as these are considerably more sensitive than clinical measures for detecting MS activity. Recently, Sormani and colleagues in 'Surrogate endpoints for EDSS worsening in multiple sclerosis' provided a systematic review and used weighted regression analyses to examine the role of either MRI lesions or relapses as trial level surrogate outcomes for disability. We build on this work by developing a Bayesian three-level model, accommodating the two surrogates and the disability endpoint, and properly taking into account that treatment effects are estimated with errors. Specifically, a combination of treatment effects based on MRI lesion count outcomes and clinical relapse was used to develop a study-level surrogate outcome model for the corresponding treatment effects based on disability progression. While the primary aim for developing this model was to support decision-making in drug development, the proposed model may also be considered for future validation. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Division of Biostatistics, University of California Berkeley, Berkeley, 94720-7358, CA, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pozzi
authors.affiliation: Statistical Methodology, Development, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmidli
authors.affiliation: Statistical Methodology, Development, Novartis Pharmaceuticals Corporation, East Hanover, 07936-1080, NJ, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Ohlssen
mesh_terms: D001499:Bayes Theorem; D015415:Biomarkers / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers
keywords: Bayesian hierarchical modeling; clinical trials; drug development decisions; multivariate meta-analysis; surrogate outcome