Keeping up with CFTR modulator eligibility

The availability of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators has transformed outcomes for people with cystic fibrosis (pwCF). Eligibility, conferred initially by clinical trial data, has evolved through advances in in vitro 'theratyping' and use of real‑world evidence. Since ivacaftor's approval for a single gating variant in 2012, eligibility has broadened to over 180 variants with the highly effective therapies elexacaftor/tezacaftor/ivacaftor and recently launched vanzacaftor/tezacaftor/deutivacaftor. Regulatory authorities have increasingly accepted non‑traditional evidence, notably the FDA's 2017 ivacaftor extension based on cell‑based assays and, in 2025, the EMA's decision to extend elexacaftor/tezacaftor/ivacaftor to people ≥2 years with at least one non class I variant. However, clinical response remains variable, influenced in part by baseline characteristics, pharmacokinetics, pharmacogenetics, and environmental exposures. We outline evolving approaches to determining eligibility and strategies to improve methods to predict, verify, and monitor clinical response in an era of personalised medicine.