Dose optimization in FDA oncology drug approvals: Factors associated with observing exposure-efficacy relationships.

Abstract

e15127 Background: Exposure–response analysis has been recognized as a fundamental component in dose selection, optimization, and regulatory decision making across all phases of drug development. Our previous research has identified that when exposure–efficacy (E-E) relationships are observed, the likelihood of being subject to postmarketing requirements (PMRs) or postmarketing commitments (PMCs) related to dose optimization is significantly reduced. For successful E-E analyses, this study primarily evaluated the association between the number of dose levels used in E-E analyses and the observation of E-E relationships, and secondarily identified factors associated with observing E-E relationships in single-dose analyses. Methods: New oncology drugs approved in the United States between 2010 and 2024 were evaluated. Data were sourced from the publicly available Drugs@FDA database. The association between observation of E-E relationships and evaluated dose levels was assessed using odds ratios with 95% confidence intervals. Factors associated with observation of E-E relationships in a single dose evaluation were analyzed using logistic regression. Results: The analysis included 139 drugs, with 86 (61.9%) using a single dose and 53 (38.1%) using multiple dose levels for E-E analysis (Table 1). The association between observation of E-E relationship and multi-dose E-E analysis was statistically significant (χ² = 7.71, df = 1, p = 0.0055), with an odds ratio of 2.78. (95% CI: 1.34–5.78). In the analysis of factors associated with observing E-E relationships in a single dose evaluation, antibody based targeted drugs were identified as a significant factor using a logistic regression model. Conclusions: Our study revealed that the E-E relationships were evaluated using a single-dose for the majority of drugs (61.9%). E-E analysis conducted across multiple dose levels were strongly associated with a higher likelihood of observing E-E relationships. These findings highlight the importance of evaluating E-E analysis using multiple dose levels, which may help reduce the risk of being subject to PMRs and PMCs related to dose optimization. In addition, our study indicates that E-E relationships were more likely to be observed for antibody based targeted drugs, even though the analysis was conducted in a single dose level. Observation of E-E relationships and dose levels used in the analysis. 　 E-E relationships were observed E-E relationships were NOT observed Total Multiple dose levels 38 15 53 Single dose 41 45 86 E-E, exposure–efficacy.