Is recent FDA guidance on HRQoL clinical significance a barrier to clinician/patient treatment risk/benefit discussions: An example using EORTC scale endpoints in a randomized, phase 3 trial.

Abstract

e21066 Background: Recent FDA guidance on clinical significance thresholds (CSTs) may adversely affect the evaluation of EORTC endpoints, thereby altering clinician/patient discussions about treatment (Tx) risk/benefit for emerging Tx. Specifically, FDA now rejects historic CSTs for EORTC measures (e.g., Osoba, 1998 10-point change). FDA’s guidance implies that EORTC function/symptom CSTs should be ±33.331; in addition, Tx arms must separate at the CST. Few, if any, EORTC domains are likely to achieve CSTs 3 times those of Osoba (1998). Holding health-related quality of life (HRQoL) endpoints to this standard may limit detection of clinically meaningful patient-centric Tx benefits & clinician/patients dialogue about HRQoL for emerging cancer Tx. The NCI-conducted Sunitinib trial data (NCT00693992), obtained through Project DataSphere, was used to generate revised deterioration thresholds for EORTC scales under an anchor-based meaningful change approach. This this Phase 3 trial met it’s primary PFS endpoint. Evidence from this research highlights the potential implications of the FDAs position on COA-based CSTs. Methods: The Sunitinib trial was a randomized, phase 3 study comparing the efficacy & safety of Sunitinib versus placebo as a maintenance therapy in non-progressing patients following chemotherapy in advanced non-small cell lung cancer. Symptoms & HRQoL were measured by EORTC LC13. The analysis population consisted of 107 patients in the HRQoL substudy completing the QLQ-C30 Global Health/QoL scale (GHS). The GHS was used to categorize patients into: no change (0 pt. change), deterioration (≤-1 pt. change) & improvement (≥1 pt. change). Deterioration thresholds were estimated as the mean LC13 scale change-scores & visualized with empirical cumulative distribution functions (eCDFs). Results: See Table. Within this population, interpretable mean deterioration CSTs were found Dyspnea, Diarrhea, and Nausea/Vomiting. At these CSTs, Tx arms separated in eCDFs except for Dyspnea. However, while Dyspnea & Diarrhea CSTs exceeded Osoba’s CSTs, none met the FDA criterion of + 33.33 points change. Conclusions: The LC13 scores had interpretable CSTs; evidence suggests FDA’s CST criterion may be unachievable for EORTC scales & may thereby affect HRQoL endpoints. This research was limited by the use of the GHS as an anchor variable rather than a PGIS. The main risk is that FDA’s CST criterion may limit the characterization of truly meaningful Tx benefits for patients & clinician communication with patients about HRQoL for emerging Tx. Clinical trial information: NCT00693992. [Table: see text]