{"entity":{"id":"idea-tr1-randomised-dose-comparison-before-pivotal","kind":"idea","name":"Randomise at least two doses in phase 2 before any pivotal trial","aka":[],"tldr":"Cancer drugs are usually tested at the highest dose patients can stand, and that dose sticks for life. Comparing two or more doses head-to-head before the big trial would find doses that work as well with fewer side effects.","summary":"Following FDA's Project Optimus, sponsors run randomised parallel-dose cohorts (typically two or three doses spanning the exposure-response range) in phase 2 with efficacy, tolerability and PK endpoints, before selecting the dose for registrational trials. Precedent: the post-approval randomised comparison of sotorasib 960 mg versus 240 mg, which found similar efficacy. The proposal makes randomised dose comparison the expectation, with regulators declining to accept single-dose pivotal trials for targeted agents without it.","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"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["kinase-inhibitors"],"targets":[],"drugs":["sotorasib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-dose-optimisation","b-toxicity-qol"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Agents with randomised dose comparison will be approved at lower doses than their maximum tolerated dose in a substantial fraction of cases, with lower rates of dose reduction and discontinuation in real-world use, and without loss of efficacy.","rationale":"Targeted agents and biologics often plateau in efficacy well below the maximum tolerated dose; MTD-based dosing is a legacy of cytotoxics. Dose reductions after approval are frequent and costly.","test":"Compare real-world dose-reduction and discontinuation rates for agents approved after randomised dose comparison versus contemporaneous agents approved at MTD.","maturity":"being-tested-at-scale","actor":"regulator","cost":"medium","horizonYears":3},"route":"/ideas/idea-tr1-randomised-dose-comparison-before-pivotal/","neighbours":{"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"drug":[{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"bottleneck":[{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"paper":[{"id":"paper-drug-dosing-conundrum-nejm-2021","kind":"paper","name":"FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high","route":"/key-papers/paper-drug-dosing-conundrum-nejm-2021/"}],"roadmap":[{"id":"trial-modernisation-roadmap","kind":"roadmap","name":"Trial modernisation roadmap: the randomised trial → platforms and adaptive designs → decentralised, pragmatic and always-on","route":"/roadmaps/trial-modernisation-roadmap/"}]}}