Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials
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(2020) 20:211
RESEARCH ARTICLE
Open Access
Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials Junhao Liu1,2, Jo Wick1, Renee’ H. Martin3, Caitlyn Meinzer3, Dooti Roy4 and Byron Gajewski1*
Abstract Background: Monitoring and reporting of drug safety during a clinical trial is essential to its success. More recent attention to drug safety has encouraged statistical methods development for monitoring and detecting potential safety signals. This paper investigates the potential impact of the process of the blinded investigator identifying a potential safety signal, which should be further investigated by the Data and Safety Monitoring Board with an unblinded safety data analysis. Methods: In this paper, two-stage Bayesian hierarchical models are proposed for safety signal detection following a pre-specified set of interim analyses that are applied to efficacy. At stage 1, a hierarchical blinded model uses blinded safety data to detect a potential safety signal and at stage 2, a hierarchical logistic model is applied to confirm the signal with unblinded safety data. Results: Any interim safety monitoring analysis is usually scheduled via negotiation between the trial sponsor and the Data and Safety Monitoring Board. The proposed safety monitoring process starts once 53 subjects have been enrolled into an eight-arm phase II clinical trial for the first interim analysis. Operating characteristics describing the performance of this proposed workflow are investigated using simulations based on the different scenarios. Conclusions: The two-stage Bayesian safety procedure in this paper provides a statistical view to monitor safety during the clinical trials. The proposed two-stage monitoring model has an excellent accuracy of detecting and flagging a potential safety signal at stage 1, and with the most important feature that further action at stage 2 could confirm the safety issue. Keywords: Two-stage monitoring, Bayesian hierarchical method, Blinded and Unblinded safety data
Background Interest in monitoring and reporting drug safety during the execution of a clinical trial and careful monitoring throughout the development of a drug from pre-clinical to post-marketing stages, has grown at a remarkable rate in the past decade. This attentiveness to drug safety has inspired statistical methods development for monitoring * Correspondence: [email protected] 1 Department of Biostatistics & Data Science, University of Kansas Medical Center, Mail Stop 1026, 3901 Rainbow Blvd, Kansas City, KS 66160, USA Full list of author information is available at the end of the article
and detecting potential safety signals during trial execution. Proposed methods include Bayesian and frequentist models for blinded and unblinded safety monitoring for randomized clinical trials [1, 2]. Blinding is the process of concealing treatment-related information from the people involved in a clinical trial, such as the sponsors, participants, and researchers. Blinding preserves the int
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