P305: FDA’s Proactive Inclusion of PRO-CTCAE, an Exploratory Measure, in an Oncology Drug Label: Opportunity or Risk for Industry?
Poster Presenter
Jaymin Patel
HEOR
AESARA United States
Objectives
To highlight the first instance of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), an exploratory endpoint, being included in drug labeling approved by the Food and Drug Administration (FDA).
Method
This case study examines PRO-CTCAE’s history and FDA’s evolving stance. We reviewed FDA records, label, and related publications to assess factors influencing the inclusion of PRO-CTCAE, an exploratory endpoint of the INAVO120 study, into the label.
Results
The National Cancer Institute developed PRO-CTCAE in 2014 to capture patient-reported symptomatic adverse events (AEs) alongside clinician CTCAE. Over the next several years (2015-2020), the measure was increasingly used in trials but mostly descriptive, with no standardization. In 2021, the FDA began to push for dose optimization in oncology with Project Optimus, balancing efficacy and tolerability and elevating the importance of patient-reported outcomes (PROs). Recent FDA guidances for PROs calls for structured PRO-CTCAE reporting with severity, frequency, and worsening trends.
Inavolisab received breakthrough therapy designation from the FDA for the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor (HR)-positive/HER2-negative breast cancer. Inavolisab is the first oncology product with PRO-CTCAE as an exploratory endpoint included into the FDA label. The overall patient-reported side-effect impact was measured using the single Modified Bother Item (MBI). At baseline, 70% of patients in the inavolisab group (inavolisab, palbociclib, and fulvestrant) and 76% in the placebo group (palbociclib, and fulvestrant) reported no bother from side effects. By Cycle 2, Day 15, this dropped to 25% in the inavolisab group and 53% in the placebo group. Over 31 treatment cycles, patients in the inavolisab group reported more side effect bother than those in the placebo group. However, patients in both treatment groups maintained their baseline health-related quality of life (HRQoL), physical functioning, and role functioning, as assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30), with no difference observed between the inavolisib and placebo groups.
Conclusion
This case suggests that PRO-CTCAE may become a standard expectation in FDA oncology labels, reflecting the agency’s commitment to incorporating patient experience data. This aligns with FDA policies on enhancing labeling to better inform healthcare providers and patients, as well as guidance on PRO data collection in cancer trials. However, to ensure fair balance, patient experience data should be incorporated in a way that contextualizes both benefits and risks. For example, with inavolisib, higher symptom burden (25% vs. 53% reporting "no bother") was reported despite stable quality of life, likely due to efficacy benefits offsetting adverse events.
Future trials should assume regulatory scrutiny on patient-reported tolerability. Proactive planning is key with phase 1/2 trials used to identify tolerability risks early and alignment with FDA expectations on structured PRO-CTCAE reporting and positioning within an overall benefit-risk narrative. More broadly, other PRO measures or quality of life assessments such as EORTC QLQ-C30 and Functional Assessment of Cancer Therapy – General Population (FACT-GP5)/MBI could be incorporated in clinical trials to provide a holistic patient impact.
Justification for exclusion may be needed. While symptomatic AEs assessed by PROs are intended to complement, not replace, standard safety data, avoiding PRO-CTCAE may require strong rationale as FDA seems to be encouraging inclusion. Thus, early engagement with regulators to control the data presentation strategy may be a key element to include in oncology clinical development programs.
