Abstract
Drug dose appropriateness is one of the most discussed issues in regulatory reviews. We analyzed dose determinations during Food and Drug Administration (FDA) drug reviews to determine whether there were changes between the proposed and approved doses of new molecular entities (NMEs), including cases where postmarketing dose-finding studies were requested, and explored the factors associated with these decisions. Of the 218 eligible NMEs approved between 2018 and 2022, 28 drugs (13%) had modifications to the proposed dose or requested additional postmarketing assessments, 20 of which were to a lower dose ("downward," 9.2%) and five were to a higher dose ("upward," 2.3%). Multinomial logistic regression analysis suggested that products that used the Accelerated Approval program were more likely to undergo downward modification (relative risk ratio (RRR) = 5.73). In addition, the fact that a dose/exposure-response relationship was observed for safety, but not efficacy, was associated with an increased probability of downward modifications (RRR: 4.27). In contrast, the use of pharmacodynamic biomarkers for dose setting and designation of Priority Review was associated with decreased probabilities of downward change (RRR: 0.405 and 0.195, respectively). Infectious disease drugs went through more upward modifications than those in the other therapeutic categories. This study revealed that dose "optimization" occurs during the FDA's review for drug approval and that not only product characteristics but also factors related to the drug review and approval process are associated with the decisions to modify or question the dose, suggesting considerations for the presence of compelling evidence and restrictions in data availabilities.