OnCo
ideasIdea

Make pre-approval dose optimisation an ICH standard so it is done once worldwide

The FDA now asks companies to find the right dose of a cancer drug before approval. If every regulator asked the same way, companies would do it once and doses would match worldwide.

FDA's Project Optimus (guidance finalised 2024) expects randomised dose comparison before approval for oncology drugs; other regulators have not formally adopted it, so sponsors face different expectations and may launch different doses in different regions. The proposal is an ICH efficacy guideline codifying dose-optimisation expectations for oncology (randomised comparison of at least two doses, exposure-response, tolerability endpoints) so that one programme serves all regions and approved doses converge.

Hypothesis
After adoption, the proportion of new oncology approvals with different approved doses in different regions falls to near zero, and the rate of post-approval dose reductions in labels falls by half.
Rationale
Historical maximum-tolerated-dose development left many targeted drugs approved at doses later shown to be excessive (sotorasib and several kinase inhibitors). Divergent regional expectations multiply cost and delay adoption of the better dose.
What would test it
ICH concept paper and expert working group; track regional dose divergence and label dose changes for products developed under the guideline against the prior five-year cohort.
Maturity
early clinical
Who has to act
regulator
Cost to try
Small (under $1M)
Years to first evidence
4
Bottlenecks it attacks
  • Regulatory divergence between regions · Regulatory divergence means a drug approved in one country can take years to reach another, or never arrive.
  • Wrong doses · Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.

Key papers

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reviewNew England Journal of Medicine 2021changed practice
FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high

The dose on the label is often not the best dose for patients; it is the highest one that was tolerable for a few weeks. Project Optimus means new cancer drugs should arrive with evidence on dose, and it gives clinicians licence to consider dose reduction for toxicity. For older drugs, the evidence gap persists.

Connected

4top

Pages like this

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drugs

1
ApprovedSmall-molecule inhibitor (KRAS G12C)
Sotorasib · Lumakras

bottlenecks

2
Regulatory divergence between regionsWrong doses

key papers

1
FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high