# A formal regulatory route for validating a biomarker on archived trial samples

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

## TL;DR

Completed trials have stored samples. Testing a new biomarker on them with the plan written in advance is nearly as good as a new trial and far cheaper, but regulators have no clear route to accept it.

## Summary

The prospective-retrospective design (Simon, Paik and Hayes) uses archived samples from a completed randomised trial with a pre-specified analysis plan to validate a predictive biomarker. It rescued KRAS testing for anti-EGFR antibodies and Oncotype DX. Regulators accept it case by case. A published guidance with requirements (sample availability above a threshold, pre-registered analysis plan, independent statistical execution) would make the route predictable and encourage sponsors to bank and share samples.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Guidance will double the number of biomarker label changes supported by prospective-retrospective analyses within five years and cut the average time from biomarker hypothesis to label from six years to three.
- Rationale: The design is accepted in the methodological literature and has produced several practice changes; the barrier is regulatory uncertainty and sample access.
- Proposed test: Draft and publish guidance; track submissions and outcomes; compare with the preceding five years.
- 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

- ideas: [Rescue the biological samples from failed trials for biomarker research](https://onco.cc/ideas/idea-tr2-failed-trial-biobank/)
- trials: [RxPONDER (SWOG S1007)](https://onco.cc/trials/rxponder/), [TAILORx](https://onco.cc/trials/tailorx/)
- drugs: [Oncotype DX](https://onco.cc/drugs/oncotype-dx/)
- terms: [Companion diagnostic](https://onco.cc/terms/companion-diagnostic-term/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Failures are hidden](https://onco.cc/bottlenecks/b-negative-results/)
- key papers: [Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue](https://onco.cc/key-papers/paper-fernandez-jama-oncol/)

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