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

Source: https://onco.cc/ideas/idea-tr2-marker-stratified-default/  
OnCo record `idea-tr2-marker-stratified-default` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed test: Fund marker-negative cohorts in five ongoing enrichment trials and analyse interaction effects; compare with historical label revisions.
- Maturity: early-clinical
- Actor: regulator

## Sources

- Bottleneck evidence (Biomarkers are not validated or standardised): Fernandez et al., Examination of low ERBB2 protein expression in breast cancer tissue (JAMA Oncology 2022): https://doi.org/10.1001/jamaoncol.2021.7239

## Connected records

- terms: [Companion diagnostic](https://onco.cc/terms/companion-diagnostic-term/), [Hazard ratio (HR)](https://onco.cc/terms/hazard-ratio/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/)
- ideas: [Lock the biomarker cut-off before phase 3, and publish it](https://onco.cc/ideas/idea-tr2-cutpoint-lock/), [Randomised trials to test whether biomarker-negative patients really do not benefit](https://onco.cc/ideas/idea-tr2-biomarker-negative-arms/)
- technologies: [Companion diagnostics](https://onco.cc/technologies/companion-diagnostic/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- key papers: [Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue](https://onco.cc/key-papers/paper-fernandez-jama-oncol/)
- roadmaps: [Diagnostics roadmap: stains → gene panels → blood tests that decide treatment](https://onco.cc/roadmaps/diagnostics-roadmap/)

---
JSON: https://onco.cc/api/v1/entities/idea-tr2-marker-stratified-default.json