Longitudinal assessment of the impact of multiple switches between a biosimilar and its reference product on efficacy parameters.

Patients, physicians, and health care providers in Europe have more than 10 years of experience with biosimilars. However, there are still debates if switching between a biosimilar and its reference product influences the efficacy of the treatment. In this paper, we address this uncertainty by developing a formal statistical test that can be used for showing that switching has no negative impact on the efficacy of biosimilars. For that, we first introduce a linear mixed-effects model that is used for defining the null hypothesis (switching influences the efficacy) and the alternative hypothesis (switching has no influence on the efficacy). Using this as the foundation of our work, we propose several approaches for testing for changes in the efficacy of the treatment due to switching and discuss the properties of these tests in an extensive simulation study. It is shown that all these methods have advantages and disadvantages and the decision regarding which method is preferred depends on the expectation of a switching assessment. To demonstrate the applicability of the methods in practice, the approaches were applied to the data of the EGALITY study, which compares the reference product Enbrel® (Amgen) with the approved biosimilar Erelzi® (Sandoz).