Author:
Gendy Joseph M.,Nomura Naomi,Stuart Jeffrey N.,Blumenthal Gideon
Abstract
Abstract
Background
Dose optimization is a focal point of many US Food and Drug Administration (FDA) drug approvals. We sought to understand the impact of the FDA’s Postmarketing Commitments/Postmarketing Requirements (PMCs/PMRs) on dose optimization and prescriber labeling for oncology drugs.
Methods
Publicly available information was aggregated for all FDA oncology drug approvals between January 1, 2010, and December 31, 2022. Study completion dates were compared to product labeling before and after PMC/PMR fulfillment dates to evaluate labeling changes associated with dose-related PMCs/PMRs. Data were analyzed individually (2010–2015 and 2016–2022) due to differences in available information.
Results
From 2010 to 2015, 14 of 42 (33.3%) new molecular entities (NMEs) had dose-related PMCs/PMRs, with 6 of 14 (42.9%) resulting in a relevant label change. From 2016 to 2022, of the 314 new or supplemental applications approved, 21 had dose-related PMCs/PMRs (6.7%), which trended upward over time; 71.4% of dose-related PMCs/PMRs were NMEs. Kinase inhibitors (KIs) and antibody/peptide drug conjugates (ADCs/PDCs) were the most affected drug classes. Ten of the 21 approvals with dose-related PMCs/PMRs fulfilled their dosing PMCs/PMRs, and 3 of the 10 (30%) had relevant label changes.
Conclusion
Most dose-related PMRs/PMCs were issued for NMEs. Of these, KIs and ADCs/PDCs were highly represented, reflecting their novelty and greater uncertainty around their safety profile. PMC/PMR issuance broadly increased over time. With the implementation of the FDA’s Project Optimus in 2021, it remains to be seen whether fewer dose-related PMCs/PMRs emerge in future due to enhanced dose optimization in the premarketing setting.
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Public Health, Environmental and Occupational Health,Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Reference15 articles.
1. Lu D, Lu T, Stroh M, Graham RA, Agarwal P, Musib L, et al. A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities. Cancer Chemother Pharmacol. 2016;77(3):459–76. https://doi.org/10.1007/s00280-015-2931-4.
2. Shah M, Rahman A, Theoret MR, Pazdur R. The drug-dosing conundrum in oncology - When less is more. N Engl J Med. 2021;385(16):1445–7. https://doi.org/10.1056/NEJMp2109826.
3. Shen J, Swift B, Mamelok R, Pine S, Sinclair J, Attar M. Design and conduct considerations for first-in-human trials. Clin Transl Sci. 2019;12(1):6–19. https://doi.org/10.1111/cts.12582.
4. Gormley N: FDA Introductory Comments: Oncologic Drugs Advisory Committee Meeting. [Slides 182–183]. https://www.fda.gov/media/157837/download (2022). Accessed April 11 2023.
5. Booth B, Zhu H: Project Optimus – FDA’s “new” dose optimization & selection paradigm in oncology drug development. Simulations plus webinar. [Slide 21]. https://www.simulations-plus.com/wp-content/uploads/OncologyDoseSLPSept2022_FINAL.pdf Accessed April 10 2023.