# Randomise at least two doses in phase 2 before any pivotal trial

Source: https://onco.cc/ideas/idea-tr1-randomised-dose-comparison-before-pivotal/  
OnCo record `idea-tr1-randomised-dose-comparison-before-pivotal` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- FDA Oncology Center of Excellence: Project Optimus: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus

## Connected records

- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- drugs: [Sotorasib](https://onco.cc/drugs/sotorasib/)
- bottlenecks: [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- key papers: [FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high](https://onco.cc/key-papers/paper-drug-dosing-conundrum-nejm-2021/)
- roadmaps: [Trial modernisation roadmap: the randomised trial → platforms and adaptive designs → decentralised, pragmatic and always-on](https://onco.cc/roadmaps/trial-modernisation-roadmap/)

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