A review of patient-reported outcomes used for regulatory approval of oncology medicinal products in the European Union between 2017 and 2020.

Introduction: Cancer and corresponding available treatments are associated with substantial symptoms and functional limitations. In this context, collection of patient-reported outcomes (PRO) in clinical trials gained special interest and is recommended by regulatory authorities. Within clinical trials framework, PRO may provide evidence to support medicines approval, labeling and marketing claims. This study aims to analyze the existing evidence based on PRO as part of new oncology indications receiving positive opinions issued by the European Medicines Agency (EMA) between 2017 and 2020 and to identify PRO related label claims granted. Methodology: Oncology medicinal products and indications approved by the European Commission following a positive opinion from the EMA between 2017 and 2020 were identified. European Public Assessment Report (EPAR) and Summary of Product Characteristics (SmPC) were reviewed for each medicinal product to identify use of PRO and PRO label claims. Results: A total of 128 oncology indications, corresponding to 76 medicines, were approved; of those, 100 (78.1%) included PRO in the confirmatory clinical trials. Thirty-seven indications were supported by double-blind randomized trials and the remainder 63 by open-label trials. Out of the 104 confirmatory trials analyzed, PRO were defined as a secondary endpoint in 60 studies (57.7%), exploratory in 31 (29.8%) and as both in 13 (12.5%). In total, 54 different PRO measures (PROM) were used, of those 41 (75.9%) were disease-specific measures. Nevertheless, PROM selected relied on the EORTC (41.3%), FACIT (17.1%) and EQ-5D (29.2%) measures. A total of 76 indications (59.4%) had PRO reviewers comments included in the EPAR, however only 22 indications (17.8%) included label claims in the SmPC. The reasons identified in the EMA assessment supporting the exclusion of PRO claims were described for 34 indications (44.7%). Conclusions: Despite growing recognition of the value of PRO data for the development of improved cancer therapies, PRO implementation remains challenging. The main reasons identified in our study are related with study design, missing data, study conduct and PROM selection.

International validation of the EORTC QLQ-CLL17 questionnaire for assessment of health-related quality of life for patients with chronic lymphocytic leukaemia.

Selecting the most appropriate chronic lymphocytic leukaemia (CLL) treatment is challenging. Patient-reported health-related quality of life (HRQoL) is therefore a critical aspect to consider. This international study by the European Organization for Research and Treatment of Cancer (EORTC) tested the psychometric properties of a newly developed measure for CLL patients: the EORTC QLQ-CLL17 to supplement the core questionnaire (EORTC QLQ-C30). Patients with CLL (n = 341) from 12 countries completed the QLQ-C30, QLQ-CLL17 and a debriefing questionnaire. Sociodemographic and clinical data were recorded from medical records. A high percentage (30%-66%) reported symptoms and/or worries (e.g. aches/pains in muscles, lack of energy and worry/fears about health). Confirmatory factor analysis showed an acceptable to good fit of the 17 items on the three scales (i.e. symptom burden, physical condition/fatigue and worries/fears about health and functioning). Completion took on average 8 min. Test-retest and convergent validity was demonstrated. The QLQ-CLL17 differentiated between patients with an Eastern Cooperative Oncology group (ECOG) performance of 0 versus 1-3 (p's < 0.01 and clinically relevant). The newly developed EORTC QLQ-CLL17 will increase sensitivity of HRQoL assessment in patients with CLL. Implementation of this questionnaire both in clinical research and practice will help to generate unique clinically relevant data to better inform CLL treatment decision-making.

Real-world effectiveness of pembrolizumab in previously treated non-small cell lung cancer: A population-based cohort study.

PURPOSE: Immunotherapy is promising for lung cancer treatment, although at significant financial impact. The aim of this study was to evaluate the effectiveness and the efficacy-effectiveness gap of pembrolizumab in previously treated non-small cell lung cancer (NSCLC). METHODS: A population-based ambispective cohort study was conducted. Cases of interest were identified through the National Cancer Registry database and additional data sources. Patients aged ≥18 years, diagnosed with NSCLC and exposed to pembrolizumab, between 23 June 2016 and 31 October 2018, as second or later lines of treatment for advanced disease were included. Patients were followed-up until death or cut-off date (30 April 2019). Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), event-free survival (EFS), and adverse events (AEs) leading to treatment discontinuation. The efficacy-effectiveness gap was evaluated comparing results with clinical trial data. RESULTS: A total of 181 patients were included. Median age was 63 years (range 33-94); 74.6% were male. Median treatment duration was 5.6 months (interquartile range: 1.4-10.4) and, at cut-off date, treatment had been discontinued in 141 patients, mainly due to disease progression. Median OS was 13.0 months (95% confidence interval [CI] 9.3-15.9) and 1-year OS was 53.1% (95% CI 45.2%-60.3%). Median PFS was 5.6 months (95% CI 4.6-7.2), median EFS was 4.7 months (95% CI 3.2-6.0), and treatment was discontinued due to AE in 8.3% of cases (n = 15). The efficacy-effectiveness gap seems to favor pembrolizumab use in clinical practice. CONCLUSION: Real-world data suggest the performance of pembrolizumab to reflect the clinical trial outcomes in previously treated NSCLC.

Intensive Monitoring Studies for Assessing Medicines: A Systematic Review.

Introduction: Intensive monitoring (IM) is one of the methods of post-marketing active surveillance based upon event monitoring, which has received interest in the current medicines regulatory landscape. For a specific period of time, IM involves primary data collection and is actively focused on gathering longitudinal information, mainly safety, since the first day of drug use. Objectives: To describe IM systems and studies' data published over 11-years period (2006-2016). Specifically, we reviewed study population/event surveillance, methodological approaches, limitations, and its applications in the real-world evidence generation data. Methods: We completed a systematic search of MEDLINE and EMBASE to identify studies published from 2006 to 2016, that used IM methodology. We extracted data using a standardized form and results were analyzed descriptively. The methodological quality of selected studies was assessed using the modified Downs and Black checklist. Results: From 1,400 screened citations, we identified 86 papers, corresponding to 69 different studies. Seventy percent of reviewed studies corresponded to established IM systems, of which, more than half were prescription event monitoring (PEM) and modified-PEM. Among non-established IM systems, vaccines were the most common studied drugs (n = 14). The median cohort size ranged from 488 (hospitals) to 10,479 (PEM) patients. Patients and caregivers were the event data source in 39.1% of studies. The mean overall quality score was similar between established and non-established IM. Conclusions: Over the study period, IM studies were implemented in 26 countries with different maturity levels of post-marketing surveillance systems. We identified two major limitations: only 20% of studies were conducted at hospital-level, which is a matter of concern, insofar as healthcare systems are facing a lack of access to new medicines at ambulatory care level. Additionally, IM access to data of drug exposure cohorts, either at identification or at follow-up stages, could somehow constitute a barrier, given the complexity of managerial, linkable, and privacy data issues.