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For most modern precision medicines, however, maximum tolerated dose is far greater than the minimum dose needed to achieve maximal benefit, leading to unnecessary side effects. Regulatory change may decrease maximum tolerated dose\u2019s predominance by enforcing dose optimization of new drugs. Dozens of already approved cancer drugs require re-evaluation, however, introducing a new methodologic and ethical challenge in cancer clinical trials. In this article, we assess the history and current landscape of cancer drug dose finding. We provide a set of strategic priorities for postapproval dose optimization trials of the future. We discuss ethical considerations for postapproval dose optimization trial design and review three major design strategies for these unique trials that would both adhere to ethical standards and benefit patients and funders. We close with a discussion of financial and reporting considerations in the realm of dose optimization. Taken together, we provide a comprehensive, bird\u2019s eye view of the postapproval dose optimization trial landscape and offer our thoughts on the next steps required of methodologies and regulatory and funding regimes.<\/jats:p>","DOI":"10.1177\/17407745231213882","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T03:27:05Z","timestamp":1703647625000},"page":"340-349","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Optimizing the doses of cancer drugs after usual dose finding"],"prefix":"10.1177","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2973-3040","authenticated-orcid":false,"given":"Garth W","family":"Strohbehn","sequence":"first","affiliation":[{"name":"Veterans Affairs Center for Clinical Management Research, Ann Arbor, MI, USA"},{"name":"Division of Medical Oncology, Lieutenant Colonel Charles S. Kettles VA Medical Center, Ann Arbor, MI, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA"},{"name":"Institute for Health Policy and Innovation, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter M","family":"Stadler","sequence":"additional","affiliation":[{"name":"Section of Hematology\/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8545-9133","authenticated-orcid":false,"given":"Philip S","family":"Boonstra","sequence":"additional","affiliation":[{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA"},{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"Ratain","sequence":"additional","affiliation":[{"name":"Section of Hematology\/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA"},{"name":"Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA"},{"name":"Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2023,12,27]]},"reference":[{"key":"bibr1-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01371"},{"key":"bibr2-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1853"},{"key":"bibr3-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju429"},{"key":"bibr4-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx045"},{"key":"bibr5-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1186\/s13012-015-0211-7"},{"key":"bibr6-17407745231213882","volume-title":"ICER white paper: strengthening the accelerated approval pathway","author":"Kaltenboeck A","year":"2021"},{"key":"bibr7-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2019.0462"},{"key":"bibr8-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.9415"},{"key":"bibr9-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-019-00074-z"},{"key":"bibr10-17407745231213882","unstructured":"ODAC nixes three cancer drug indications, citing dose uncertainty, 2022. https:\/\/cancerletter.com\/the-cancer-letter\/20220930_3\/ (accessed 10 April 2023)"},{"key":"bibr11-17407745231213882","volume-title":"Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases: guidance for industry","author":"Oncology Center of Excellence"},{"key":"bibr12-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00221-0"},{"key":"bibr13-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2109826"},{"key":"bibr14-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2104846"},{"key":"bibr15-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.0610"},{"key":"bibr16-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2022.4226"},{"key":"bibr17-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1191\/1740774505cn094oa"},{"key":"bibr18-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2022-063436"},{"key":"bibr19-17407745231213882","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2021.7047"},{"key":"bibr20-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(21)00251-5"},{"key":"bibr21-17407745231213882","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-022-06755-5"},{"key":"bibr22-17407745231213882","unstructured":"Blumenthal GM, Jain L, Loeser A, et al. 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