{"entity":{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","aka":[],"tldr":"Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.","summary":"Oncology inherited from cytotoxic chemotherapy the assumption that more drug is better, so phase 1 trials escalate to the maximum tolerated dose over a few weeks in a few dozen patients and that dose becomes the label. Targeted agents, antibodies, ADCs and immunotherapies saturate their targets far below toxicity, and chronic dosing exposes patients to months of grade 2 toxicity that the 28-day dose-limiting-toxicity window never measured. The consequences are dose reductions and discontinuations in a third or more of patients on many oral targeted agents, avoidable cost, and occasionally drugs that fail because nobody can stay on them. The FDA's Project Optimus (2021) and its 2024 guidance now require randomised comparison of at least two doses before registration, and trials such as PERSEPHONE show that duration can be halved without loss of efficacy. Dosimetry-based individualisation is the parallel challenge in radioligand therapy.","asOf":"2026-09-08","links":[{"label":"FDA Oncology Center of Excellence, Project Optimus","url":"https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus"},{"label":"Shah, Rahman, Theoret & Pazdur, The drug-dosing conundrum in oncology: when less is more (NEJM 2021)","url":"https://doi.org/10.1056/NEJMp2109826"},{"label":"Earl et al., 6 versus 12 months of adjuvant trastuzumab (PERSEPHONE, Lancet 2019)","url":"https://doi.org/10.1016/S0140-6736(19)30650-6"}],"tags":[],"related":["fda-approvals","idea-shortened-venetoclax","idea-desmoid-intermittent-dosing","idea-net-dosimetry-prrt","idea-total-body-pet-dosimetry","idea-tr1-public-dose-reduction-trials-of-approved-drugs","idea-tr1-weight-based-vs-flat-dosing-trials","idea-tr1-extended-interval-checkpoint-dosing","idea-tr1-therapeutic-drug-monitoring-for-oral-tkis","idea-tr1-intermittent-dosing-to-delay-resistance","idea-tr1-adaptive-therapy-randomised-phase-2","idea-tr1-start-low-titrate-up-oral-agents","idea-tr1-pre-emptive-pharmacogenomic-testing","idea-tr1-model-based-dose-finding-with-late-toxicity","idea-tr1-adc-dose-and-schedule-optimisation","idea-tr1-dose-evidence-statement-in-label","idea-tr1-patient-reported-toxicity-dose-algorithms","idea-tr1-food-effect-dose-reduction","idea-tr1-factorial-dose-finding-for-combinations","idea-tr1-organ-impairment-pk-before-approval","idea-tr1-low-dose-immunotherapy-for-lmic","idea-tr1-response-adapted-dose-reduction","idea-moon-individualised-dosing-all-oral-drugs","idea-cost-low-dose-abiraterone-food","idea-cost-low-dose-immunotherapy-trials","idea-cost-optimus-legacy-drugs","idea-cost-extended-interval-default","idea-cost-shorter-course-trials"],"cancers":["breast-her2-positive","breast-hr-positive","nsclc","aml","neuroendocrine","sarcoma"],"sections":[],"technologies":["radioligand-therapy","prrt","adc","kinase-inhibitors","cdk46-inhibitor"],"targets":[],"drugs":["sotorasib","abemaciclib","nirogacestat","venetoclax","trastuzumab"],"companies":["finaldose","amgen"],"institutions":[],"pathways":[],"terms":["dosimetry","ild","alpha-vs-beta"],"trials":["monarch-3","persephone","apt-trial"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"trials","severity":"major","metrics":[{"label":"Patients requiring dose reduction of abemaciclib for adverse events in first-line MONARCH 3","value":"~43%","source":"Goetz et al., JCO 2017","url":"https://doi.org/10.1200/JCO.2017.75.6155"},{"label":"Six vs twelve months of adjuvant trastuzumab in HER2-positive breast cancer (PERSEPHONE): 4-year disease-free survival","value":"89.4% vs 89.8% (non-inferior)","source":"Earl et al., Lancet 2019","url":"https://doi.org/10.1016/S0140-6736(19)30650-6"}],"causes":["Phase 1 designs optimise for speed and identify the maximum tolerated dose rather than the optimal biological dose.","Dose-limiting toxicity is assessed in one cycle, missing cumulative and chronic toxicities.","Sponsors have no commercial incentive to study lower doses or shorter durations after approval.","Regulators historically accepted a single dose in registration trials.","Pharmacokinetic variability between patients is large but dosing is rarely individualised."],"currentEfforts":["FDA Project Optimus and the 2024 final guidance on dose optimisation require sponsors to compare multiple doses before registration.","PERSEPHONE, SOLD and Short-HER established that shorter adjuvant trastuzumab is non-inferior for many patients.","The CodeBreaK 100 randomised 960 mg vs 240 mg sotorasib comparison, required by the FDA, is the model for post-approval dose re-evaluation.","Dosimetry-personalised PRRT and radioligand therapy trials replace fixed activity with absorbed-dose-based dosing.","Intermittent and stop-and-restart dosing is being tested for nirogacestat in desmoid tumours and for venetoclax in AML.","Finaldose and academic pharmacometrics groups apply model-informed precision dosing to oncology drugs."],"successLooksLike":"Every new oncology drug is registered with a dose chosen by randomised comparison, the rate of dose reductions and discontinuations for toxicity on oral targeted agents falls below 20%, and duration of therapy is tested rather than assumed."},"route":"/bottlenecks/b-dose-optimisation/","neighbours":{"collection":[{"id":"fda-approvals","kind":"collection","name":"FDA Oncology Approvals (OCE) & Novel Drug Approvals","route":"/collections/fda-approvals/"}],"idea":[{"id":"idea-tr1-dose-evidence-statement-in-label","kind":"idea","name":"A 'dose evidence' panel in every label: how many doses were tested, and how","route":"/ideas/idea-tr1-dose-evidence-statement-in-label/"},{"id":"idea-tr1-mandatory-older-adult-cohort","kind":"idea","name":"A mandatory over-70s cohort with geriatric assessment in every pivotal trial","route":"/ideas/idea-tr1-mandatory-older-adult-cohort/"},{"id":"idea-bio1-adaptive-therapy-platform","kind":"idea","name":"A multi-cancer platform trial of adaptive (dose-holiday) therapy","route":"/ideas/idea-bio1-adaptive-therapy-platform/"},{"id":"idea-bio1-upfront-bypass-combination","kind":"idea","name":"Add the second drug on day one when the escape route is 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