{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:53:45Z","timestamp":1791658425305,"version":"4.3.4"},"reference-count":24,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:p>Optimal dosing of oncological drugs is historically determined based on the \u201chigher is better\u201d paradigm. However, a paradigm shift in optimal dose selection has occurred in the development of new modalities, including molecularly targeted drugs, antibody drugs, and immunotherapies. In 2021, Project Optimus was launched by the Food and Drug Administration Oncology Center of Excellence to reform the dose optimization and dose selection paradigm in oncology drug development. In August 2024, \u201cOptimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases\u201d was published, encouraging randomized evaluation of the benefit\/risk profile of a range of doses before initiating a registration trial. Although Project Optimus offers general guidance on dose optimization, it does not specify which early clinical data requires a more cautious approach to dose optimization. This is the first comprehensive study to investigate newly approved oncology drugs by the FDA over a long period and to identify the risk factors for postmarketing requirement or commitment to dose optimization, using logistic regression analysis. Our findings show that when the labeled dose is the maximum tolerated dose, the percentage of adverse reactions leading to treatment discontinuation is increased, and an exposure\u2010safety relationship is established, the risk for postmarketing requirement or commitment to dose optimization is increased. Our study will provide actionable, data\u2010driven insights into dose optimization strategies by objectively and quantitatively evaluating risk factors. These findings will serve as valuable guidance for designing more effective early\u2010phase trials, complementing the FDA Project Optimus guidance.<\/jats:p>","DOI":"10.1002\/cpt.3722","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T02:39:09Z","timestamp":1747795149000},"page":"823-830","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dose Optimization in Oncology Drug Development: Risk Factors for Postmarketing Requirements and Commitments"],"prefix":"10.1002","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0086-7643","authenticated-orcid":false,"given":"Hiroe","family":"Kitagaki","sequence":"first","affiliation":[{"name":"Regulatory Science, Graduate School of Pharmaceutical Science Meiji Pharmaceutical University  Tokyo Japan"},{"name":"Early Clinical Development Clinical Operations Astellas Pharma Inc.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8584-0521","authenticated-orcid":false,"given":"Kentaro","family":"Takeda","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Murai","sequence":"additional","affiliation":[{"name":"Regulatory Science, Graduate School of Pharmaceutical Science Meiji Pharmaceutical University  Tokyo Japan"},{"name":"Department of Pharmacy Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0117-3961","authenticated-orcid":false,"given":"Hideki","family":"Maeda","sequence":"additional","affiliation":[{"name":"Regulatory Science, Graduate School of Pharmaceutical Science Meiji Pharmaceutical University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"e_1_2_12_1_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199120030-00002"},{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14662"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2014.40"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.08.002"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2109826"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.282542"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.245"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3298"},{"key":"e_1_2_12_9_1","unstructured":"Project optimus reforming the dose optimization and dose selection paradigm in oncology. <https:\/\/www.fda.gov\/about\u2010fda\/oncology\u2010center\u2010excellence\/project\u2010optimus> (2003). Accessed January 11 2024."},{"key":"e_1_2_12_10_1","unstructured":"Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases guidance for industry. <https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/optimizing\u2010dosage\u2010human\u2010prescription\u2010drugs\u2010and\u2010biological\u2010products\u2010treatment\u2010oncologic\u2010diseases> (2024). Accessed October 14 2024."},{"key":"e_1_2_12_11_1","unstructured":"Drugs@FDA:FDA\u2010approved drugs. <https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm> (2024). Accessed September 1 2024."},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0040296"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-022-04444-0"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2208"},{"key":"e_1_2_12_15_1","unstructured":"Friends of cancer research white paper. Optimizing dosing in oncology drug development. <https:\/\/friendsofcancerresearch.org\/wp\u2010content\/uploads\/Optimizing_Dosing_in_Oncology_Drug_Development.pdf> (2021)."},{"key":"e_1_2_12_16_1","first-page":"13","article-title":"RIP MTD: FDA to require sponsors to determine optimal dosage before initiating pivotal trials in cancer","volume":"47","author":"Goldberg P.","year":"2021","journal-title":"Cancer Lett."},{"key":"e_1_2_12_17_1","first-page":"15","article-title":"Optimize the dose: an optimal step forward for FDA","volume":"47","author":"Ratain M.J.S.G.","year":"2021","journal-title":"Cancer Lett."},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2023.103913"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.153"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-2585"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.2470"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1864"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.20.00257"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1144056"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3722","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T04:16:59Z","timestamp":1758946619000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":24,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/cpt.3722"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3722","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,20]]},"assertion":[{"value":"2025-02-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}