{"entity":{"id":"idea-tr1-tolerability-estimands","kind":"idea","name":"Define tolerability endpoints as rigorously as efficacy endpoints","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-08","links":[{"label":"PRO-CTCAE (NCI)","url":"https://healthcaredelivery.cancer.gov/pro-ctcae/"},{"label":"ICH efficacy guidelines (E9(R1) estimands)","url":"https://www.ich.org/page/efficacy-guidelines"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["irae"],"trials":[],"people":[],"bottlenecks":["b-trial-design","b-toxicity-qol","b-dose-optimisation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","test":"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","actor":"regulator","cost":"small","horizonYears":2},"route":"/ideas/idea-tr1-tolerability-estimands/","neighbours":{"term":[{"id":"irae","kind":"term","name":"Immune-related adverse events (irAEs)","route":"/terms/irae/"}],"bottleneck":[{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"roadmap":[{"id":"trial-modernisation-roadmap","kind":"roadmap","name":"Trial modernisation roadmap: the randomised trial → platforms and adaptive designs → decentralised, pragmatic and always-on","route":"/roadmaps/trial-modernisation-roadmap/"}]}}