# Define tolerability endpoints as rigorously as efficacy endpoints

Source: https://onco.cc/ideas/idea-tr1-tolerability-estimands/  
OnCo record `idea-tr1-tolerability-estimands` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- PRO-CTCAE (NCI): https://healthcaredelivery.cancer.gov/pro-ctcae/
- ICH efficacy guidelines (E9(R1) estimands): https://www.ich.org/page/efficacy-guidelines

## Connected records

- terms: [Immune-related adverse events (irAEs)](https://onco.cc/terms/irae/)
- bottlenecks: [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- roadmaps: [Trial modernisation roadmap: the randomised trial → platforms and adaptive designs → decentralised, pragmatic and always-on](https://onco.cc/roadmaps/trial-modernisation-roadmap/)

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