OnCo
ideasIdea

Test the drug in biomarker-negative patients too, so the biomarker can be validated

Trials that only enrol patients with a positive biomarker can never prove the biomarker matters. Including a smaller biomarker-negative group would show whether the test is really needed.

Enrichment designs enrol only biomarker-positive patients and cannot estimate the interaction between marker and treatment. Marker-stratified designs (all-comers with stratified randomisation and pre-specified interaction tests) are the accepted way to validate a predictive biomarker but are rarely used because they cost more. Regulators could require a marker-negative cohort (even under-powered but pooled across trials) whenever a biomarker is proposed to restrict a label, so the restriction is evidence-based.

Hypothesis
Among drugs approved with a biomarker restriction, marker-negative cohorts will show clinically meaningful benefit in at least a fifth of cases, revealing that current enrichment designs deny treatment to patients who would benefit.
Rationale
PD-L1 cut-offs, HER2-low, and HRD have each shifted after post hoc analyses of marker-negative or unselected populations, showing that enrichment-only evidence leads to unstable labels.
What would test it
Fund marker-negative cohorts in five ongoing enrichment trials and analyse interaction effects; compare with historical label revisions.
Maturity
early clinical
Who has to act
regulator
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks

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