OnCo
ideasIdea

Define tolerability endpoints as rigorously as efficacy endpoints

Trials report side effects as a table of percentages that hides how long they lasted, how bad they felt and whether people stopped treatment. Tolerability should be measured with defined endpoints and a decision rule, like efficacy.

Protocols pre-specify tolerability estimands under ICH E9(R1): time to first dose modification, cumulative patient-reported symptom burden (PRO-CTCAE), treatment discontinuation for toxicity, and a toxicity-over-time summary, with hypotheses and analysis plans. Regulators include a tolerability summary in the label, and dose-optimisation decisions reference it.

Hypothesis
Pre-specified tolerability endpoints will change the interpretation of at least a fifth of positive phase 3 trials (identifying regimens where efficacy gains are offset by tolerability losses) and will improve concordance between label and real-world persistence.
Rationale
Maximum-grade tables ignore duration and patient perspective; PRO-CTCAE and longitudinal toxicity analyses exist but are secondary and rarely pre-specified with a decision rule.
What would test it
Apply the tolerability estimand framework to trials with existing PRO-CTCAE data and compare conclusions with the original safety tables; then mandate it for a cohort of new registrational trials.
Maturity
early clinical
Who has to act
regulator
Cost to try
Small (under $1M)
Years to first evidence
2
Bottlenecks it attacks

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