On the underreporting of health-related quality of life and regulatory approval
Authors: D. Bhamidipati, S. Anand, A. Gothwal, K. Raghav, M.J. Overman
Journal: Annals of Oncology (2019)

Recently, Marandino et al. [1.Marandino L. La Salvia A. Sonetto C. et al.Deficiencies in health-related quality of life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016.Ann Oncol. 2018; 29: 2288-2295Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar] published a systematic review highlighting the shortcomings with respect to reporting of health-related quality of life (HRQoL) in contemporary oncology trials. Notably, among the 446 randomized phase III clinical trials evaluated between 2012 and 2016, close to half (47.1%) did not assess HRQoL as an end point, which was true even for trials designed to treat advanced disease (40.1%). Surprisingly, there appeared to be no significant difference in reporting of HRQoL in the primary publication between trials with positive outcomes and negative outcomes. The omission of this important data from many trials unfortunately detracts from a thorough understanding of the risks and benefits of a given regimen. To further investigate whether this deficit in oncology clinical trials exists even within the highest tier, we performed a systematic review of randomized phase III clinical trials published between 2009 and 2018 that resulted in an FDA approval. We believe that these trials directly impact treatment practice and patient care and therefore should be held to the highest standards. A search of Food and Drug Administration (FDA) database was performed for drugs and therapies approved for treatment of solid and hematologic malignancies. The phase III clinical trials that led to FDA approval of the given therapy were identified. In total, 140 phase III trials resulted in an FDA approval for 84 distinct drugs during this time period. Of the 140 trials, 78 (56%; 95% confidence interval: 47% to 64%) reported HRQoL with 50 (64%) reporting HRQoL outcomes in the primary publication and 28 (36%) reporting HRQoL outcomes in a separate publication. This data support the findings of Marandino et al. demonstrating the low rate of HRQoL reporting even within pivotal practice changing phase III trials. About half of all these clinical trials do not report on HRQoL as an end point, undermining its value in clinical care. Interestingly, HRQoL was listed as an outcome measure on ClinicalTrials.gov in only 50% of trials, demonstrating that HRQoL reporting appears to reflect phase III trial construction rather than lack of reporting. It appears that a relatively low level of importance is placed on HRQoL measures and that lack of inclusion of HRQoL data does not appear to compromise the regulatory success of an investigational agent. It is important we continue to recognize the value of HRQoL measures, as survival outcomes do not necessarily match patients’ experience while receiving treatment [2.Kovic B. Jin X. Kennedy S.A. et al.Evaluating progression-free survival as a surrogate outcome for health-related quality of life in oncology.JAMA Intern Med. 2018; 178: 1586-1596Crossref PubMed Scopus (68) Google Scholar, 3.Hwang T.J. Gyawali B. Association between progression-free survival and patients’ quality of life in cancer clinical trials.Int J Cancer. 2019; 144: 1746-1751Crossref PubMed Scopus (45) Google Scholar]. These measures become increasingly important for advanced/metastatic disease where symptom improvement may outweigh marginal gains in length of life for patients. In a reflection of the importance of HRQoL, both the American Society of Clinical Oncology and European Society of Medical Oncology have integrated patient reported outcomes into their treatment evaluation tools [4.Schnipper L.E. Davidson N.E. Wollins D.S. et al.American Society of Clinical Oncology Statement: a conceptual framework to assess the value of cancer treatment options.J Clin Oncol. 2015; 33: 2563-2577Crossref PubMed Scopus (677) Google Scholar, 5.Cherny N.I. Sullivan R. Dafni U. et al.A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol. 2015; 26: 1547-1573Abstract Full Text Full Text PDF PubMed Scopus (532) Google Scholar]. We believe the burden now falls on regulatory agencies to properly incentivize the inclusion and reporting of this valuable data. None declared.