Post-marketing label changes in dosing information of biopharmaceuticals-different from small molecules?

Background: Establishing the optimal dose of a drug is of clear importance for both efficacy and safety. Dose changes in the label occur frequently (∼20%) in the post-marketing phase of new substances; most often a downward adjustment related to safety concerns. However, limited information about dose changes is available for biopharmaceuticals. Objectives: To evaluate post-marketing label changes in dosing information of biopharmaceuticals. Methods: Biopharmaceuticals authorised between 2007 and 2014 via the European Medicines Agency (EMA) were included in this cohort study. The follow-up time consisted of the period from marketing authorisation until 31 December 2016 or date of withdrawal of the marketing authorisation. The primary outcome of the study was defined as label change in dosing information for the initially approved indication; an increase or decrease in daily dose or a change in dosing frequency (e.g. 200 mg every 2 weeks to 400 mg every 4 weeks). The assessment history as retrieved from the EMA website was used to determine if a label change in dosing information of a product had occurred. Incidence of changes, type of change and mean time to change were assessed. As a secondary outcome, changes in dosing during extension of the indication were assessed. Results: A total of 71 biopharmaceuticals were authorised during the study period. The mean followup time was six years (SD: 3). Dosing changed for the initial indication in the label during follow-up for seven products (cumulative incidence 10%). In three of the seven products the change concerned an increase in dose. Also, in three products a change in dosing frequency was identified. For the remaining product a recommendation was added that therapy could be initiated with or without a loading dose. The mean time to a label change was four years (SD: 2, range 1-7 years). The indication was extended 59 times within 30 products (42%). The dosing for the extended indication differed from the initial dosing in 32 out of these 59 extensions (54%). Extension of indication did not influence the dosing of the initial indication. Conclusions: This study showed that in 10% of the biopharmaceuticals the dosing information in the label was changed an average of four years after marketing authorisation. In contrast with small molecules, these dose changes included dose increases and changes in dosing frequency. This difference may be explained by the different mechanism of action of biopharmaceuticals.