Multistate modeling of clinical hold in randomized clinical trials
Autor: | Alexandra Nießl, Jan Beyersmann, Anja H. Loos |
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Rok vydání: | 2018 |
Předmět: |
Statistics and Probability
Counterfactual thinking Lung Neoplasms Time Factors Computer science 01 natural sciences law.invention 010104 statistics & probability 03 medical and health sciences 0302 clinical medicine Randomized controlled trial law Carcinoma Non-Small-Cell Lung Overall survival Humans Pharmacology (medical) 030212 general & internal medicine Progression-free survival 0101 mathematics Randomized Controlled Trials as Topic Pharmacology Actuarial science Models Statistical Proportional hazards model Disease progression Intention to Treat Analysis Clinical trial Treatment Outcome Clinical Trials Phase III as Topic Research Design Censoring (clinical trials) Data Interpretation Statistical Disease Progression Immunotherapy |
Zdroj: | Pharmaceutical statisticsReferences. 19(3) |
ISSN: | 1539-1612 |
Popis: | 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. |
Databáze: | OpenAIRE |
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