Health-related quality of life (QoL) in randomized phase III trials in oncology: Association between results of QoL, results of primary endpoint and drug approval.
Authors: Paratore Chiara , Schiavone Rocco , Zichi Clizia , Caglio Andrea , Gamba Teresa , Bombaci Sebastiano , Vellani Giorgio , Marandino Laura , Perrone Francesco , Di Maio Massimo 
Published: June 2024

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Background: scientific community and regulatory agencies have shown a growing interest on QoL, although the inclusion and reporting of QoL analysis in clinical trials is still suboptimal. Methods: we previously published a meta-research study of phase III randomized clinical trial (RCT) in patients with solid neoplasms treated with systemic therapy, published from 2012 to 2021 (BMJ Oncology 2023;2:e000021). For the present analysis, we selected the RCT conducted in the advanced setting, integrating the database with results of QoL and of primary endpoints, and with info about regulatory approval. The main outcome was the analysis of correlation of QoL results with study primary endpoint (EP1), namely overall survival (OS) or progression free survival (PFS). Among secondary outcomes, the availability of QoL results was reported for treatments approved by EMA/FDA, with description of time-trends. Results: 592phase III RCTpublished from 2012 to 2021 were included: 322 (54.4%) published in 2012-2016 and 270 (45.6%) in 2017-2021. 151 RCT (25.5%) were conducted in gastro-intestinal cancers, 138 (23.3%) in thoracic cancers, 71 (12%) in breast cancer, 79 (13.3%) in genito-urinary cancers. Experimental treatment was chemotherapy in 322 studies (54.4%), targeted therapies in 331 (55.9%), immunotherapy in 94 (15.9%) and hormone therapy in 52 (8.8%). OS was the EP1 in 298 clinical trials (50.3%) and PFS in 304 clinical trials (51.4%), with an overlap for 79 studies (13.3%) with multiple primary endpoints. 124 RCT (41.6%) with EP1 OS reported a positive result in EP1. Among these, QoL analysis was positive for experimental treatment in 62 studies (50%), without statistically significant difference or unfavourable in 30 (24.2%) and not available in 32 (25.8%). In the 182 studies (59.5%) with EP1 PFS and a positive result in EP1, QoL analysis was positive for experimental arm in 77 studies (42.3%), without statistically significant difference or unfavourable in 49 (26.9%) and not available in 56 (30.8%). FDA drug approvals were reported for 143 studies (24.2%). Among them, QoL results were positive for experimental arm in 101 studies (70.6%), negative in 19 (13.3%), absent in 23 (16.1%). Similarly, 142 studies (24%) were associated to EMA approval: positive QoL in 101 studies (71.1%), negative in 21 (14.8%) and absent in 20 (14.1%). The percentage of FDA and EMA approvals associated with the availability of positive QoL data increased from 2012-2016 to 2017-2021. Namely, the proportion of approvals with available QoL positive results increased from 56.5% to 81.5% (p<0.001) among FDA approvals, and from 55.4% to 84.4% (p<0.001) among EMA approvals. Conclusions: in many cases, a positivity in OS or PFS is not accompanied by the demonstration of QoL benefit. The temporal trend of positive QoL results among treatments approved by regulatory agencies is encouraging.