Underreporting of Symptomatic Adverse Events in Phase I Clinical Trials

Abstract

Background: Clinician reporting of symptomatic adverse events (AEs) in phase I trials uses the Common Terminology Criteria for Adverse Events (CTCAE). The utility of the patient-reported outcomes (PROs) version of the CTCAE (PRO-CTCAE) in this setting is unknown. This prospective, observational study compared patient- and clinician-reported symptomatic AEs in phase I patients.

Methods: Phase I study-eligible patients at Princess Margaret were surveyed with the PRO-CTCAE full-item library (78 symptomatic AEs) at baseline (BL), mid-cycle 1, and mid-cycle 2 (C2). Patient and trial characteristics, best response, and survival data were collected. Presence or absence of patient- (PRO-CTCAE) or clinician-reported symptomatic AEs were compared (kappa) at defined timepoints and overall (BL+ mid-cycle 1 + C2).

Results: Of 292 patients approached from May 2017 to January 2019, a total of 265 (90.8%) were consented, with 243 (91.7%) evaluable and 552 PRO-CTCAE surveys (completion rate = 98.7%) included in analyses. Evaluation of overall patient-reported symptomatic AEs identified 50 PRO-CTCAE and 11 CTCAE items with 10% or greater reporting frequency. Nineteen CTCAE items were reported as 1% or less despite matched PRO-CTCAE items reporting as 10% or greater. Underreported categories included sexual health, bodily emissions, and cognition. Clinician- relative to patient-reporting frequency (ratio) demonstrated 9 symptomatic AEs with a 50-fold or more lower clinician reporting rate. Overall patient-clinician agreement for individual symptomatic AEs ranged from poor (κ = 0.00-0.19) to moderate (κ = 0.40-0.59), with discordance driven by lack of clinician reporting. Dyspnea (κ = 0.54) and peripheral neuropathy (κ = 0.63) at BL and limb edema (κ = 0.55) at C2 demonstrated the highest patient-clinician agreement.

Conclusions: Poor to moderate patient-clinician agreement for symptomatic AEs suggests clinician underreporting in phase I trials. Analyses of severity and interference PRO categories are ongoing.

Figure 1.

Patient and clinician reporting of symptomatic adverse events (AEs). Top: Frequently (≥10%) reported patient (patient-reported outcomes version of Common Terminology Criteria for Adverse Events [PRO-CTCAE]) AEs relative to clinician (CTCAE) symptomatic AEs. Bottom: Infrequently (≤1%) reported clinician (CTCAE) events relative to frequently (≥10%) reported patient (PRO-CTCAE) symptomatic AEs.

Figure 2.

Patient to physician ratio of symptomatic adverse event (AE) categories. Ratio of overall patient symptomatic AE (patient-reported outcomes version of Common Terminology Criteria for Adverse Events [PRO-CTCAE]) reporting frequency relative to matched clinician symptomatic AE (CTCAE) reporting frequency by individual category.

Figure 3.

Kappa agreement scores for individual symptomatic adverse event (AE) categories. Agreement (kappa) scores between patient- (patient-reported outcomes version of Common Terminology Criteria for Adverse Events [PRO-CTCAE]) and clinician- (CTCAE) reported symptomatic AEs overall and by timepoint. Kappa agreement scores are classified based on poor (0.00-0.19), fair (0.20-0.39), moderate (0.40-0.59), good (0.60-0.79), and very good (0.80-1.00). PRO-CTCAE items with a frequency of 10% or greater were included in kappa analysis. Symptomatic AEs with agreement less than 0.1 (kappa) on 3 or more categories have been omitted. C1 = mid-cycle 1; C2 = mid-cycle 2.