Patient-Reported Outcomes in Clinical Trials Leading to Cancer Immunotherapy Drug Approvals From 2011 to 2018: A Systematic Review

Abstract

Background Patient-reported outcomes (PROs) promote patient-centeredness in clinical trials; however, in the field of the rapidly emerging and clinically impressive immunotherapy, data on PROs are limited. Methods We systematically identified all immunotherapy approvals from 2011 through 2018 and assessed the analytic tools and reporting quality of associated PRO reports. For randomized clinical trials (RCTs), we developed a novel 24-point scoring scale: the PRO Endpoints Analysis Score (PROEAS) based on 24 criteria derived from the recommendations of the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) Consortium. Results We assessed 44 trial publications supporting 42 immunotherapy approvals. PROs were published for 21 of the 44 (47.7%) trial publications. Twenty-three trials (52.3%) were RCTs and 21 (47.7%) pertained to single-arm trials. The median time between primary clinical outcomes publications and their corresponding secondary PRO publications was 19 months (IQR= 9–29). Of the 21 PRO reports, 4 (19.0%) reported a specific hypothesis, and most (85.7%) used descriptive statistics. Three (3 of 21 [14.3%]) studies performed a control for type I error. As for RCTs, 14 of 23 (60.9%) published PRO data including 13 (56.5%) that published a secondary dedicated manuscript. Half of these 14 trials scored < 13 points on the 24-point PROEAS. The mean score was 12.71 (range= 5–17; SD = 3.71), and none met all the recommendations of the SISAQOL Consortium. Conclusion Suboptimal reporting of PROs occurs regularly in cancer immunotherapy trials. Increased efforts are needed to maximize the value of this data in cancer immunotherapy development and approval.

Analysis of patient reported outcomes included in the registrational clinical trials of nivolumab for advanced non-small cell lung cancer

“…In general, several studies have raised concerns about PRO assessments in randomized clinical trials. [ 38 , 39 ] There have been concerns on reporting bias when measuring PROs in open-label trials, although some of these concerns have been challenged. [ 40 , 41 ] Given that patients may have increased expectations about the nivolumab, open-label studies may compel more patients to complete questionnaires and/or positively rank nivolumab.…”

The current issues and future perspective of artificial intelligence for developing new treatment strategy in non-small cell lung cancer: harmonization of molecular cancer biology and artificial intelligence

“…Accordingly, the development of patient selection strategies for individualized immunotherapy is an important issue. In recent decades, comprehensive analyses of tumor specimens combined with detailed clinical information have been performed in various clinical trials [ 60 ]. Although these large profiling datasets have the potential to benefit the discovery of novel prediction methods of immune therapeutic activity for individual patients, translational and reverse translational research has not been adequately conducted.…”

A 15 Year Review (2006-2020) of Patient-Reported Outcomes (PRO) in United States Oncology Product Labeling and Trends in Sponsor Size and Oncology Experience

“…The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQC30), EuroQol 5-dimensional questionnaire (EQ-5D), and Functional Assessment of Cancer Therapy: General (FACT-G) are the most commonly used general cancer measurement tools observed in oncology clinical trials. 6,7,[9][10][11][12] While the FDA does not specify which assessment tools to use, their 2009 Guidance for Industry for PRO outcome measures to support labeling claims does provide the characteristics they should contain. 3 Acceptability of PRO tools by health authorities varies.…”

“…15 Despite this, missing data, including 6 baseline data, is one of the primary reasons FDA rejects PRO data to support label claims. 6,7,9,10 Oncology patients tend to have significant health complications and complex treatment plans which involve a high number of office visits and the length of time to complete a HRQL is an increased burden on the patient. Collection of baseline data also means that study sponsors must also have the PRO instrument in place at the time of study initiation, which is not always the case, especially for products which get approval based on earlier phase studies.…”