Important sources of variability in clinical studies of neutralizing antibodies against interferon beta.

Interferon (IFN) beta treatment of relapsing-remitting multiple sclerosis (RRMS) stimulates production of neutralizing antibodies (NAbs) in some patients. However, clinical data supporting the hypothesis that NAbs to IFN beta adversely affect patient outcomes are not consistent across multiple studies or different forms of IFN beta. Only the PRISMS trial has produced data showing a negative impact of NAbs to IFN beta-1a (Rebif) across multiple study endpoints. No such data are available for IFN beta-1b (Betaseron) despite completion of a large registry study. Biological factors affecting the development of NAbs to IFN beta include protein structure, product formulation, administration frequency and/or dosing, and patients' immunological responses. Technical factors affecting interpretation of clinical trial data on NAbs include inadequate randomization; differences in the methods used to measure NAbs and in definitions of NAb positivity; selection of NAb-positive patient subpopulations according to titer and duration of NAb response; lack of power to detect differences in patient subgroups; and different trial durations. Given the complexity of NAb studies, it is not possible to generalize from current data regarding the potential impact of NAbs on the clinical efficacy of all IFN beta therapies. Differences between IFN beta products and their specific trials should be considered when evaluating the evidence on this topic.