ideasIdea

Lock the biomarker cut-off before phase 3, and publish it

Companies sometimes choose the biomarker threshold that makes their trial look best after seeing the data. Requiring the threshold to be fixed and published before the big trial starts prevents this.

Cut-points for continuous biomarkers (PD-L1 percentages, HER2-low boundaries, ctDNA thresholds) are frequently selected from phase 2 data with multiple thresholds explored, and sometimes revised during phase 3. Regulators could require that the phase 3 protocol specify the cut-point and the assay version, derived from an independent training set, with the derivation report deposited in the trial registry before enrolment.

Hypothesis

Trials with locked and published cut-points will show smaller shrinkage of the biomarker treatment interaction between phase 2 and phase 3 than trials with adaptive or post hoc cut-points.

Rationale

Optimism bias from cut-point selection is a known statistical phenomenon; pre-registration is the standard remedy for analytic flexibility.

What would test it

Audit the last 30 biomarker-restricted approvals for cut-point derivation and revision; implement the requirement and compare interaction estimates in subsequent trials.

Maturity

early clinical

Who has to act

regulator

Cost to try

Small (under $1M)

Years to first evidence

Bottlenecks it attacks

Biomarkers are not validated or standardised · Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.
Trial design, endpoints and cost · A phase 3 trial takes years and hundreds of millions of dollars, and often answers a question that has already moved on.

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Lock the biomarker cut-off before phase 3, and publish it

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