定义和收集患者报告的治疗耐受性，为药物开发提供信息

Defining and Collecting Patient-Reported Treatment Tolerability Table of contents Background1Definingtreatment2FDAregulatory3PrecedenceinKeyconsiderationstudiesBeyondPRO-CTCAE:BuildingantPracticalrecommendations12ReferencesAboutthe16 Background The pharmaceutical industry is increasingly incorporating an assessment ofpatient-reported treatment tolerability in their clinical trials, mainly driven by theFDA requirements. Treatment tolerability is a multidimensional concept that has Defining treatment tolerability Treatment tolerability has undergone significantevolution in its definition over the past decades. TheInternational Conference on Harmonisation (ICH) E9guidance (1998) originally defined tolerability as “The degree to which symptomatic and non-symptomatic adverse eventsassociated with the product’s administration affect the ability or desireof the patient to adhere to the dose or intensity of therapy. A complete This definition underlines several key elements: Regulatory guidances and measurement tools the known mechanism of action of study agents.PRO-CTCAE is intended to complement, not replace, The FDA and EMA have emphasized the importanceof incorporating tolerability considerations into drugdevelopment, as reflected in their recent guidance •Single-Item Global Measures: To assess overall side effect impact, the FDA supports the In its recent draft reflection paper on Patient ExperienceData released in September 2025, the EMA acknowledgesthe value of patient-relevant disease and/or treatment »FACT GP5:“I am bothered by side-effects oftreatment”, from the Functional Assessment of CancerTherapy (FACT) item library6, and outcomes, including symptomatic adverse events andtheir tolerability.4They emphasize the importance ofearly patient engagement and collection of the patientperspective to provide a more comprehensive view of the »EORTC Q168:“To what extent have you beentroubled with side effects from your treatment?”, Including a single overall bother item helps capture theoverall impact of treatment and serves as a valuable These regulatory recommendations mark a shift fromrelying solely on clinician-reported safety data (e.g,CTCAE), in order to provide a fuller picture of treatment The FDA also recognizes the value of “collecting robustpatient input on symptoms and other aspects of theircondition that matter most to patients” including In oncology, the FDA recommends symptomatic AEs andoverall side effect impact be systematically collectedand analyzed as core PROs in cancer clinical trials.1Their •PRO-CTCAE (Patient-Reported Outcomes version ofthe Common Terminology Criteria for Adverse Events):Developed by the National Cancer Institute (NCI), thePRO-CTCAE library enables direct patient reporting Precedence in tolerability labeling claims granted by the FDA Two FDA label claims including tolerability endpoints wererecently granted by the FDA for selpercatinib (Retevmo)and inavolisib (Itovebi). These are the first labels includingpatient-reported comparative side effect impact and overallside effect bother. These cases demonstrate regulatoryopenness to descriptive patient-reported tolerability data The FACT GP5 single item (“I am bothered by side effectsof treatment”) was used to compare the two treatmentsfor medullary thyroid cancer in an open-label design.The mean proportion of time with high side effect bother “The clinical benefit of selpercatinib was supported by a pre-specifiedanalysis of patient-reported comparative side effect impact; patients in theselpercatinib arm reported less time with severe side effect bother than those Patient-reported overall side effect impact was evaluated weekly in 222 patients (RETEVMO N = 145; cabozantinibor vandetanib N=77) who received at least one dose of treatment by at least 6 months prior to the data cutoff dateand responded to the Functional Assessment of Cancer Therapy item GP5 (FACT GP5). Patient-reported overall side Patient-reported overall side effect impact results for LIBRETTO-531 are provided in Table 22. On October 10, 2024, the FDA approved inavolisib (Itovebi,Genentech, Inc.) with palbociclib and fulvestrant for adultswith Hormone Receptor (HR)-positive, human epidermalgrowth-factor receptor 2 (HER2)-negative, locally advancedor metastatic breast cancer. Patient-reported toxicitieswere assessed using PRO-CTCAE items in a double-blind,placebo-controlled phase 3 trial (INAVO120)10. The Itovebi’s The label noted “at baseline the proportion of patients withMBI responses of “not at all” were 70% in the ITOVEBI withpalbociclib and fulvestrant arm and 76% in the placebowith palbociclib and fulvestrant arm. At Cycle 2 Day 15, theproportion of patients with MBI responses of “not at all”were 25% in the ITOVEBI with palbociclib and fulvestrant These findings were Included in Section 6 (AdverseReactions/Section 6.1. clinical trial experience) of the labelcomplementing the CTCAE safety findings. This is aligned While sponsor