Exposure– and Dose–response Analyses in Dose Selection and Labeling of FDA-approved Biologics

Purpose Biological drug products, or products derived from living cells, represent an increasingly important part of the pharmaceutical market. Despite this, little is known about how sponsors determine the dose to be studied in registrational trials or to be proposed in labeling for biologics. We examined how exposure–response and dose–response analyses were used to determine dosing in pivotal trials or the labeling for all biologics approved by the Center for Drug Evaluation and Research, the US Food and Drug Administration (FDA) between 2003 and 2016. Methods We extracted relevant characteristics of each biologic from its review package by FDA. We used descriptive statistics to characterize the rationale for the selected dose(s) in registration trials, with a particular focus on the role of exposure–response/dose–response analyses. We also examined how exposure–response/dose–response analyses were used to support the labeling dose and the basis for postmarketing requirements or commitments related to dose optimization. Findings A total of 79 biologics license applications were examined. Dose selection in registrational trials was more often attributed to clinical efficacy (73% of applications) than to clinical safety (42%). The dosing of products whose dose was apparently selected based on clinical efficacy was often (72%) determined by the dose–response relationship. In support of doses that were described in labeling, exposure–response analyses for efficacy were performed more commonly (53%) than dose–response analyses (21%). This trend was apparent after 2012. Implications This is the first study to summarize the justification of dose selection and the labeled dose of biologics approved by the FDA. Dose–response analyses have been often used as the rationale for dose selection of registrational studies, although exposure–response analyses are becoming more prevalent in support of the dosing guidelines in labeling.