Abstract
BackgroundWith the growth in use of biotherapic drugs in various medical fields, the occurrence of anti-drug antibodies represents nowadays a serious issue. This immune response against a drug can be due either to pre-existing antibodies or to the novel production of antibodies from B-cell clones by a fraction of the exposed subjects. Identifying genetic markers associated with the immunogenicity of biotherapeutic drugs may provide new opportunities for risk stratification before the introduction of the drug. However, real-world investigations should take into account that the population under study is a mixture of pre-immune, immune-reactive and immune-tolerant subjects.MethodIn this work, we propose a novel test for assessing the effect of genetic markers on drug immunogenicity taking into account that the population under study is a mixed one. This test statistic is derived from a novel two-part semiparametric improper survival model which relies on immunological mechanistic considerations.ResultsSimulation results show the good behavior of the proposed statistic as compared to a two-part logrank test. In a study on drug immunogenicity, our results highlighted findings that would have been discarded when considering classical tests.ConclusionWe propose a novel test that can be used for analyzing drug immunogenicity and is easy to implement with standard softwares. This test is also applicable for situations where one wants to test the equality of improper survival distributions of semi-continuous outcomes between two or more independent groups.
Highlights
With the growth in use of biotherapic drugs in various medical fields, the occurrence of anti-drug antibodies represents nowadays a serious issue
We propose a novel test that can be used for analyzing drug immunogenicity and is easy to implement with standard softwares
This test is applicable for situations where one wants to test the equality of improper survival distributions of semi-continuous outcomes between two or more independent groups
Summary
With the growth in use of biotherapic drugs in various medical fields, the occurrence of anti-drug antibodies represents nowadays a serious issue This immune response against a drug can be due either to pre-existing antibodies or to the novel production of antibodies from B-cell clones by a fraction of the exposed subjects. If early studies about drug immunogenicity assessment have mainly relied upon response-based endpoints, time-to-event analyses are more and more often recommended for taking into account the dynamic of ADA production For such studies, subjects that have not been previously exposed to a particular BP are followed up for a certain period of time after the first BP administration. The main outcome is the first time of ADA detection after the initial drug administration and the objective is to identify factors that are related to these time-to-events [3, 4]
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