1. Multistate modeling of clinical hold in randomized clinical trials.
- Author
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Nießl A, Beyersmann J, and Loos A
- Subjects
- Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung therapy, Data Interpretation, Statistical, Disease Progression, Humans, Immunotherapy, Intention to Treat Analysis statistics & numerical data, Lung Neoplasms immunology, Lung Neoplasms mortality, Lung Neoplasms therapy, Time Factors, Treatment Outcome, Clinical Trials, Phase III as Topic statistics & numerical data, Models, Statistical, Randomized Controlled Trials as Topic statistics & numerical data, Research Design statistics & numerical data
- Abstract
A clinical hold order by the Food and Drug Administration (FDA) to the sponsor of a clinical trial is a measure to delay a proposed or to suspend an ongoing clinical investigation. The phase III clinical trial START serves as motivating data example to explore implications and potential statistical approaches for a trial continuing after a clinical hold is lifted. In spite of a modified intention-to-treat (ITT) analysis introduced to account for the clinical hold by excluding patients potentially affected most by the clinical hold, results of the trial did not show a significant improvement of overall survival duration, and the question remains whether the negative result was an effect of the clinical hold. In this paper, we propose a multistate model incorporating the clinical hold as well as disease progression as intermediate events to investigate the impact of the clinical hold on the treatment effect. Moreover, we consider a simple counterfactual censoring approach as alternative strategy to the modified ITT analysis to deal with a clinical hold. Using a realistic simulation study informed by the START data and with a design based on our multistate model, we show that the modified ITT analysis used in the START trial was reasonable. However, the censoring approach will be shown to have some benefits in terms of power and flexibility., (© 2019 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)
- Published
- 2020
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