Improvements in the health-related quality-of-life benefit of cancer drugs approved in China, 2005-2020: an observational study.

Research in context

Evidence before this study

We conducted a search on PubMed, Cochrane, Embase, Web of Science and China National Knowledge Infrastructure for journal publications and conference abstracts published from January 1, 2005 to December 31, 2023. The search terms included “cancer” or “oncology” and “quality of life” or “patient-reported outcomes”, with no language restrictions. Health-related quality of Life (HRQoL) assessment has gained significant recognition as an essential component of cancer treatment evaluation. Numerous clinical trials have been conducted to investigate the impact of cancer drugs on patients’ HRQoL, aiming to provide a more comprehensive understanding of treatment outcomes beyond traditional clinical endpoints like overall survival. While these trials have contributed valuable insights, the absence of a unified approach to measure and report HRQoL outcomes has resulted in variability and heterogeneity in the evidence. Extensive research has been conducted on the HRQoL in the context of cancer treatment in the past. However, there remains a gap in the literature concerning the indications of newly approved anticancer drugs in China.

Added value of this study

Through a systematic review and analysis of publicly available data, our study provides a comprehensive and up-to-date assessment of the measurement and improvement of HRQoL in newly approved cancer drugs in China. We observed that fewer than one-third of the approved cancer indications in China had shown HRQoL improvement, and the heterogeneity in HRQoL analysis and reporting hindered the evaluation of clinically relevant HRQoL improvements. These findings underscore the critical role of HRQoL assessment and analysis in clinical research and highlight the necessity to enhance standardization in HRQoL evaluation. By shedding light on the HRQoL outcomes associated with these drugs, our research adds significant value to the existing literature and can inform decision-making processes related to cancer treatment strategies, ultimately promoting patient-centred care and improving the overall well-being of cancer patients in China.

Implications of all the available evidence

All existing evidence suggests that despite the recognised importance of HRQoL, approved cancer therapies often lack evidence of HRQoL improvement. There remains significant heterogeneity in the measurement, analysis and evaluation of HRQoL. Future research on new drugs should place greater emphasis on HRQoL related studies and adopt standardised approaches to address this issue.

Introduction

For drugs treating advanced cancers, demonstrating improvements in patients’ health-related quality of life (HRQoL) is as important as the prolongation of their overall survival (OS). 1 HRQoL reflects patient subjective disease experience and perceived benefits of the therapy, capturing the true impact of cancer drugs on patient life beyond survival outcomes. 2 Therefore, regulatory agencies and healthcare professionals acknowledge the importance of incorporating patient perspectives and advocate for the inclusion of HRQoL data into assessing applications of cancer drug indications. 3 , 4 However, due to the multidimensional and subjective nature of HRQoL, the assessment and interpretation of HRQoL pose challenges. 5 Several studies have shown various deficiencies in the design and implementation of HRQoL in oncology trials, 1 , 6 , 7 including not measuring HRQoL at all, 8 under-reporting of HRQoL and delay in publication 9 as well as heterogeneity in HRQoL instruments, analysis and presentation of outcomes. 10 , 11

To help patients make well-informed treatment decisions, a clear understanding of the impact of cancer drugs on patient HRQoL is needed. However, many cancer drugs approved by regulatory agencies in the US and Europe lack evidence of HRQoL improvement. A recent study reported that among cancer indications approved by the US Food and Drug Administration (FDA) between 2000 and 2020, only 4% included documented HRQoL benefits in their approval documents. 12 Moreover, only around one-third of cancer indications granted by the European Medicines Agency (EMA) between 2009 and 2015 exhibited statistically significant improvements in HRQoL following a monitoring period of at least three years and 31% still lacked information on HRQoL assessment. 13 In particular, between 2006 and 2017, only 6% and 11% of indications approved by the FDA and EMA exhibited clinically meaningful improvements in HRQoL and one indication showed a deterioration in HRQoL. 1 In a previous study on newly approved cancer drugs in China from 2005 to 2020, nearly half of the cancer indications demonstrated significant benefits in OS. 14 However, the current state of HRQoL evidence for cancer therapies authorised in China remains poorly explored. To address these gaps and challenges, this study aimed to comprehensively characterise the HRQoL assessment and analysis of approved cancer indications in China between 2005 and 2020, exploring the magnitude of HRQoL benefits.

Methods

Data source and sample selection

Using publicly available data, we have constructed a comprehensive database including all newly approved cancer drugs and their corresponding indications for adult patients authorised by the National Medical Products Administration (NMPA) of China between January 1, 2005 and December 31, 2020. This database encompasses the generic names of the drugs, approved indications, pivotal clinical trials and relevant publications. The database creation, identification of pivotal trials and data extraction have been thoroughly described in a previous study. 14 Our reporting adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. As we utilised publicly available data and did not directly involve human participants, ethical approval and informed consent procedures were not required.

Publication identification, data extraction and measurement of HRQoL

Using study names and clinical trial identifiers (NCT number), we searched the Medline database (via PubMed), China National Knowledge Infrastructure and ClinicalTrials.gov to determine publications of pivotal trials published by December 31, 2023. We included all publications that reported HRQoL outcomes and provided information on HRQoL methodology and clinical relevance, including HRQoL instruments adopted, HRQoL analysis metrics (type of statistics analysis and presentation of results) and whether minimal clinically important difference (MCID) values were considered. In line with a previous study, we classified HRQoL instruments into three categories: generic, cancer-specific and individual-specific. 15 HRQoL analysis metrics were categorised according to the recommendations of the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) into (1) magnitude of improvement (i.e., mean change scores from baseline), (2) time to deterioration, (3) overall HRQoL scores at specific time points and (4) proportion of patients with improvement. 16 For the OS outcomes, we used previously published information and updated the data to December 31, 2023. 14 For studies reporting HRQoL information at different time points, we only included the results from the most recent or longest follow-up. Two researchers independently extracted general information regarding indications, reported HRQoL and OS outcomes and items related to HRQoL measurements and reporting. If there were discrepancies, a third researcher was consulted until consensus was reached.

Improvement in HRQoL and OS

In this cohort, we investigated whether there was evidence of HRQoL benefits for the approved indications. We only considered indications approved by randomised clinical trial (RCT) as trials without a control arm cannot provide comparative HRQoL information ( Supplement Figure S1 ). To determine whether the included indications showed HRQoL benefits, we categorised the HRQoL change into three categories: (1) improvement in HRQoL (i.e., each indication had at least one RCT that recorded statistically significant improvement in global health status score); (2) no difference (i.e., there was no statistically significant difference between the two treatment groups); (3) deterioration in HRQoL (i.e., compared with the control group, the intervention group experienced a significant decline in the global health status); or (4) no information available (i.e., HRQoL was not measured as an end point or not reported). For indications without HRQoL improvement, we further investigated whether it reported other patient-reported outcomes. As most trials used multiple instruments to measure HRQoL and cancer-related symptoms, we further determined whether there was any evidence of significant difference in patients’ symptoms and/or function for indications that did not report HRQoL improvement. We categorised the outcomes into four categories: (1) improvement in symptoms or HRQoL subdomains; (2) no improvement in symptoms or HRQoL subdomains; (3) worsening symptoms or deterioration in HRQoL subdomains; or (4) outcomes of symptoms or HRQoL subdomains not evaluable (The indicators were not assessed or reported). We considered a p-value <0.05 as indicating “statistically significant change”. In cases where p-value was not provided, we used Hazard Ratios (HR), 95% confidence intervals and textual descriptions to infer statistical significance.

We defined HRQoL improvement based on results of the global domain since it has been the most frequently reported information. This also aligned with the upgrading principle for HRQoL outcomes in the European Society of Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). 17 These comparisons were made between the intervention and control groups to assess whether the novel drug provides HRQoL benefit compared with the standard treatment. Therefore, for each RCT, we assessed the difference in HRQoL between the treatment groups while for single-arm trials, evaluation was not possible due to the lack of a control group. Following the prerequisites of ESMO-MCBS, 17 we prioritised HRQoL outcome from the trial where QoL was at least a secondary endpoint and evidence of reliability and validity of the instrument was provided. For indications that did not satisfy these criteria, we retained the optimal outcome if an indication was supported by multiple pivotal trials or if multiple instruments or analyses of HRQoL were employed in a study. 13 MCID was used to evaluate the clinical meaningful difference of HRQoL between the two treatment groups. 1 If the trial included a self-reported MCID value, it was used to determine clinical significance. In cases where the trial did not have a predefined MCID, the clinical meaningfulness was deemed unable to be assessed.

OS benefits were divided into three categories: (1) documented OS benefit (the trial showed statistically significant improvement of the treatment drug in OS); (2) documented lack of OS benefit and (3) unknown OS benefit (OS data was immature or not reported by the end of data extraction (December 31, 2023).

Statistical analysis

We used descriptive statistics to analyse the characteristics of included indications, measurement and reporting of HRQoL, treatment outcomes and changes in HRQoL over time. We reported the general characteristics of each indication, including whether HRQoL was measured as an end point in the pivotal trials, cancer type (solid tumour or haematological malignancy), mechanism of therapy and line of therapy.

Role of the funding source

This study was funded by National Natural Science Foundation of China (Grant No. 72274004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Results

Availability and reporting of HRQoL as an end point

We identified 78 approved cancer drugs corresponding to 141 indications from 2005 to 2020 in China ( Supplementary Tables S1 and S2 ). Most approved indications (n = 115, 81.6%) were supported by at least one RCT, while 26 (18.4%) were supported by single-arm or dose-optimization trials, which were excluded from our analysis due to unavailability of HRQoL information ( Supplementary Table S1 ). Among the 115 indications approved based on evidence from RCTs, 78 (67.8%) listed HRQoL as an endpoint in the pivotal trial(s) as a secondary (n = 50, 64.1%) or exploratory (n = 28, 35.9%) endpoint, with none being identified as a primary endpoint ( Table 1 ). As of the cut-off date of data collection (December 31, 2023), 46 cancer drugs corresponding to 75 indications (n = 75/115, 65.2%) had reported HRQoL information after a median follow-up of 5.3 years (range 3.0–18.8), of which 54 (72.0%) indications included Asian or Chinese cancer patients in their clinical trials ( Supplementary Table S2 ). The proportion of indications reporting HRQoL information fluctuated overtime ( Supplementary Figure S2 ). Most solid tumour indications (n = 66/98, 67.3%) and half of haematological malignancy indications (n = 9/17, 52.9%) had available HRQoL information. Indications related to kidney (n = 5/5, 100.0%), ovaries (n = 4/4, 100.0%) and brain (n = 3/3, 100.0%) had the highest rates of reporting HRQoL outcomes. The most common experimental treatment was targeted therapy (n = 79/115, 68.7%), with HRQoL information reported in nearly two-thirds of these indications (n = 50/79, 63.3%). Approximately half of indications were approved for first-line treatment (n = 63/115, 54.8%), of which 39 (n = 39/63, 61.9%) reported HRQoL information ( Table 1 ).

HRQoL improvement in indications

Among the 115 indications supported by RCTs, HRQoL benefits were observed in 33 indications (28.7%), while 39 (33.9%) showed no significant difference and only three (2.6%) demonstrated negative outcome ( Table 2 ). Of 98 indications for solid tumours, 27 (27.6%) were associated with improvement in patients’ HRQoL and six (n = 6/17, 35.3%) for haematological malignant neoplasms showed HRQoL benefit ( Table 3 ). Immunotherapy (n = 7/14, 50.0%) and hormone therapy (n = 4/8, 50.0%) were the most promising treatments for improving HRQoL whereas chemotherapy (n = 2/13, 15.4%) was the least likely to be effective in this regard. Approximately one-third of indications (n = 20/63, 31.7%) approved for the first-line therapy showed HRQoL benefits, while in the adjuvant or neoadjuvant settings, none of indications reported HRQoL benefits. Overtime, there was no noticeable shift in the composition of authorised indications with HRQoL benefits ( Supplementary Figure S3 ).

Overall, MCID was prespecified in only 54 indications (n = 54/115, 47.0%) and clinically relevant benefits could not be assessed in nearly half of these indications (n = 23/54, 42.6%) due to a lack of analysis of mean changes in HRQoL scores from baseline or incomplete data reporting. Only four indications (n = 4/115, 3.5%) showed clinically meaningful improvement in HRQoL beyond MCID, while 27 (n = 27/115, 23.5%) showed no clinically relevant benefits in HRQoL ( Table 2 ).

Cumulative evidence on HRQoL and OS benefits

Out of the approved indications, 68 (n = 68/115, 59.1%) documented OS benefit. Among these indications, 22 (n = 22/115, 19.1%) showed simultaneous improvements in both OS and HRQoL, while 21 (n = 21/115, 18.3%) exhibited improvement in OS alone (i.e., no noticeable change in HRQoL was observed). Furthermore, 34 indications (n = 34/115, 29.6%) documented lack of OS benefit, while ten (n = 10/115, 8.7%) exhibited improvement in HRQoL, 13 (n = 13/115, 11.3%) remained relatively stable in this regard and two (n = 2/115, 1.7%) experienced a decline in HRQoL. By the end of our study period, OS remained unknown for 13 indications (n = 13/115, 11.3%). Overall, 79 (n = 79/115, 68.7%) were associated with at least some improvement in HRQoL or OS whereas 36 (n = 36/115, 31.3%) did not show benefits in either HRQoL or OS ( Table 2 ).

Benefits of symptoms or HRQoL subdomains

Among the indications that did not demonstrate HRQoL benefits, five indications (n = 5/42, 11.9%) reported benefits in at least one HRQoL subdomain, with emotional functioning (n = 3/42, 7.1%) being the most frequently improved subdomain ( Supplementary Table S3 ). In addition, 11 indications (n = 11/42, 26.2%) reported improvement in at least one symptom, with pain (n = 6/42, 14.3%) being the most frequently symptom that showed improvement ( Supplementary Table S4 ).

HRQoL methodology and clinical relevance

Among 75 indications reporting HRQoL information, 63 (84.0%) reported the validity and reliability of the HRQoL instruments used ( Table 4 ). The most commonly used instruments to assess HRQoL were the European Organization for Research and Treatment of Cancer HRQoL Core Questionnaire (EORTC QLQ-C30, n = 43, 57.3%) and the European Quality of Life Five Dimensions (EQ-5D, n = 34, 45.3%, Supplementary Table S5 ). Eighteen cases (24.0%) employed only one HRQoL instrument while 57 (76.0%) used two or more simultaneously ( Table 4 ). The most common combinations were cancer specific and individual disease specific instruments (n = 23, 30.7%) or the combination of generic, cancer specific and individual disease specific instruments (n = 22, 29.3%, Fig. 1 a). The most common HRQoL metrics were mean change scores from baseline (n = 56, 74.7%) and time to deterioration (n = 35, 46.7%, Fig. 1 b and Table 4 ).

Discussion

In this study, we found limited evidence of HRQoL was available for the 115 cancer therapies supported by RCTs approved in China from 2005 to 2020. Fewer than one-third of the indications showed improvement in HRQoL and only one-fifth documented cumulative evidence of HRQoL and OS benefits. Furthermore, our results highlighted substantial heterogeneity in the use of HRQoL measurements, analysis modalities and reporting of results.

Despite increasing interest in HRQoL by clinicians and regulatory authorities, we observed that HRQoL is still under-represented in clinical trials as an endpoint. Our finding of suboptimal reporting of HRQoL outcomes for approved cancer indications in China is consistent with other studies. 9 , 18 A systematic review of phase-III cancer trials between 2012 and 2016 found that almost half of drugs for adult patients with solid tumours did not specify HRQoL outcomes in their protocols. 9 Although an updated meta-analysis showed an increase in the inclusion of HRQoL endpoints in oncology trials, the proportion of primary publications reporting HRQoL outcomes has been on the decline, depriving stakeholders of essential information for decision-making. 19 We also found that HRQoL was commonly designated as a secondary or exploratory endpoint, similar to the results of a previous study investigating newly FDA-approved cancer drugs. 6 When assessing HRQoL endpoints, type-1 error should be controlled by conducting statistical correction for multiple testing. However, most studies (47/50, 94%) did not adjust for it when they considered HRQoL as a secondary endpoint, potentially leading to inaccurate conclusions about the HRQoL endpoint. 20 Thus, interpretations of HRQoL benefits should be handled with caution. The inadequate HRQoL measurement and biased conclusions might be partly due to the multitude of measures available, each with different scoring and scaling criteria. 10 Furthermore, low patient engagement and the high cost of data collection contributed to difficulties in obtaining data. 21 In 2022, the NMPA Guideline on the Application of Patient-Reported Outcomes (PROs) in Drug Development highlighted PROs’ role as a critical indicator in drug evaluation and approval and provided guidance for sponsors to utilise PRO data. 22 Our study did not observe an improvement in the frequency of HRQoL assessment and reporting over time. One potential factor contributing to the limited inclusion of HRQoL data in publications is the rising prevalence of single-arm studies submitted to regulatory authorities. 23 In 2017, a series of regulatory reforms were initiated to encourage domestic research and promote development capacity. Alongside with a significant increase in the number of newly approved anticancer drugs, the approval of cancer indications based on single-arm trials is also on the rise. 14

Although OS has been considered as the most relevant endpoint to reflect clinical benefit, in some cases, patients with advanced cancer are even more concerned about HRQoL than OS. 24 , 25 Previous studies have consistently indicated a significant correlation between HRQoL and patient survival in cancer patients, with global HRQoL serving as a reliable predictor of prognosis. 26 , 27 , 28 Therefore, the lack of HRQoL information may make patients face difficult treatment choices. 29 We observed that fewer than one-third of the indications supported by RCTs showed HRQoL benefits, lower than findings in European and American studies. 30 , 31 Of the 53 new cancer drugs approved by the FDA and EMA between 2003 and 2013, 22 (42.0%) were associated with improvements in HRQoL. 30 Additionally, this study further identified that a minority of indications showed improvement in neither HRQoL nor OS, instead, these indications were associated with worsening symptoms or functional outcomes. These findings indicate that evidence regarding HRQoL gains for approved cancer indications remains limited and that newer therapies may not fully respond to patients’ treatment needs aligned with their values. Moreover, in addition to statistical significance, it is important to emphasise the consideration of clinical relevance when reporting and interpreting HRQoL findings. 32 Despite 47.0% of studies prespecified MCID, we were unable to assess clinically relevant benefits for nearly half of them due to a lack of analysis of changes in HRQoL scores from baseline or incomplete data reporting. Few indications (3.5%) demonstrated clinically significance improvement in HRQoL beyond MCID, similar to the indications approved by the FDA (5.6%) and EMA (11.9%). 1 These results suggest that indications showing statistical improvements in HRQoL may not always reflect clinically meaningful benefits. Hence, it is crucial to clearly predefine MCID and include clinically significance HRQoL information in publications to facilitate the evaluation of treatment tolerability and decision-making by healthcare professionals and patients. 33

The variability observed in the analysis and reporting of HRQoL poses challenges in the interpretation and comparison of study results as well as in the standardization of HRQoL assessment practices. This heterogeneity can be attributed, in part, to differences in HRQoL measurements, scoring methods and analytic strategies utilised across studies. 26 , 34 Most of the indications included in this study employed individual disease specific instruments, underscoring the importance of capturing HRQoL outcomes specific to different types of cancer. However, it is important to note that despite their widespread use, these questionnaires may not comprehensively capture treatment-specific symptoms in all therapeutic scenarios, such as adverse events associated with immunotherapy. 23 Moreover, the use of different instruments makes it challenging to compare HRQoL results across studies, hindering the synthesis of evidence. Efforts to develop and implement standardised HRQoL instruments tailored to specific cancer types as well as exploring the potential for consistent HRQoL measuring across different cancer types would facilitate better comparability of HRQoL outcomes and enhance the reliability of findings. 35 Furthermore, we identified substantial heterogeneity in the methods employed to analyse and present HRQoL outcomes. The most common modality observed in this study was the mean change in scores from baseline. While this approach provides valuable information on the trend and magnitude of HRQoL changes, it does not capture the full complexity of HRQoL outcomes. In fact, there is no single method that can fully capture HRQoL, which ideally requires a comprehensive analysis and complete reporting of results. 10 However, we found that most studies (76.0%) only presented one or two HRQoL metrics. Although the NMPA has released guidelines to facilitate the inclusion of PROs in drug clinical research, it does not offer explicit recommendations regarding HRQoL measurements and analysis indicators. 22 The SISAQOL consortium published recommendations to standardise the research design and analysis of HRQoL in clinical trials for cancer. 16 These significant advancements contribute to fostering greater consistency of HRQoL assessment and enhancing the comparability of HRQoL results.

Our study has several limitations. Firstly, only 41 of 115 indications (35.7%) satisfied the ESMO-MCBS prerequisites and we retained the most favourable HRQoL outcomes from pivotal trials where the ESMO-MCBS was inapplicable. This might introduce bias towards optimistic results and raise concerns about cases where multiple HRQoL measurements or analysis indicators were utilised. Second, as the follow-up duration is a critical factor in fully understanding patient experience, especially for drugs with long-term effects, HRQoL benefits can be best assessed by studies with more extended follow-up durations. Still, the median follow-up duration of our study was 5.3 (3.0–18.8) years, which aligns with published literature and allowed the observance of considerable patient outcomes. 36 Third, we employed the measurements identified by the authors to evaluate HRQoL outcomes. However, given the subjective nature of HRQoL, there may be inconsistencies in the aspects of HRQoL captured by different assessment instruments. Fourth, global health was not the only measure of HRQoL benefit and some studies could have disclosed statistical or clinical significance in specific subdomains of HRQoL. Fifth, our study did not consider the methodological challenges inherent in the included literature, including the risk of multiple tests and the absence of predefined hypotheses. Finally, although we conducted a comprehensive search of published literature to assess available evidence, additional HRQoL information could be disclosed in scientific meetings or confidential regulatory documents (94 of 141 indications are available). This highlights the importance of data transparency for informed decision-making by clinicians and the public.

In conclusion, our study reveals limited availability of HRQoL information for newly approved cancer drugs in China between 2005 and 2020, with less than one-third of the indications showing HRQoL benefits. This underscores the need to recognise the scarcity of available and favourable HRQoL evidence for approved cancer therapeutics in China. The heterogeneity observed in HRQoL analysis and reporting emphasises the urgency to establish guidelines to standardise HRQoL measurement and reporting. A comprehensive understanding of the impact of cancer drugs on HRQoL is essential in the regulatory approval process and clinical decision-making to promote patient-centred care.

Contributors

XG, LZ and YZ conceived and designed this study. LZ and YZ analysed the data and wrote the first draft manuscript. XG, LS and HL critically revised the manuscript for important intellectual content. LZ and YZ contributed equally to this research work. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Data sharing statement

All data used in this study are publicly available. Dr. Guan has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Declaration of interests

The authors declare that there are no conflicts of interest.

Acknowledgements

We would like to acknowledge Anita K. Wagner from Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute and Huseyin Naci from Department of Health Policy, London School of Economics and Political Science, for their contributions to excellent comments and feedback on this manuscript.

Footnotes

Supplementary data related to this article can be found at https://doi.org/10.1016/j.lanwpc.2024.101077 .

Supplementary data

Supplementary Figure and Tables

Translated Abstract

References

1. Arciero V., Delos Santos S., Koshy L., et al. Assessment of food and drug administration– and European medicines agency–approved systemic oncology therapies and clinically meaningful improvements in quality of life. JAMA Netw Open. 2021;4 doi: 10.1001/jamanetworkopen.2020.33004.

2. Haslam A., Herrera-Perez D., Gill J., Prasad V. Patient experience captured by quality-of-life measurement in oncology clinical trials. JAMA Netw Open. 2020;3 doi: 10.1001/jamanetworkopen.2020.0363.

3. Baldwin M., Spong A., Doward L., Gnanasakthy A. Patient-reported outcomes, patient-reported information: from randomized controlled trials to the social web and beyond. Patient. 2011;4:11–17. doi: 10.2165/11585530-000000000-00000.

4. Kluetz P.G., O'Connor D.J., Soltys K. Incorporating the patient experience into regulatory decision making in the USA, Europe, and Canada. Lancet Oncol. 2018;19:e267–e274. doi: 10.1016/S1470-2045(18)30097-4.

5. Velikova G., Coens C., Efficace F., et al. Health-Related Quality of Life in EORTC clinical trials — 30 years of progress from methodological developments to making a real impact on oncology practice. Eur J Cancer. 2012;10:141–149.

6. Ge C., Guo K., Li Y., et al. Analysis of patient-reported outcomes in the approval of novel oncology drugs in the United States, 2017–2022. eClinicalMedicine. 2023;59 doi: 10.1016/j.eclinm.2023.101953.

7. Teixeira M.M., Borges F.C., Ferreira P.S., Rocha J., Sepodes B., Torre C. A review of patient-reported outcomes used for regulatory approval of oncology medicinal products in the European Union between 2017 and 2020. Front Med. 2022;9 doi: 10.3389/fmed.2022.968272.

8. Hwang T.J., Gyawali B. Association between progression-free survival and patients' quality of life in cancer clinical trials. Int J Cancer. 2019;144:1746–1751. doi: 10.1002/ijc.31957.

9. 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;29:2288–2295. doi: 10.1093/annonc/mdy449.

10. Marandino L., De Luca E., Zichi C., et al. Quality-of-Life assessment and reporting in prostate cancer: systematic review of phase 3 trials testing anticancer drugs published between 2012 and 2018. Clin Genitourin Cancer. 2019;17:332–347.e2. doi: 10.1016/j.clgc.2019.07.007.

11. Fiero M.H., Roydhouse J.K., Vallejo J., King-Kallimanis B.L., Kluetz P.G., Sridhara R. US Food and Drug Administration review of statistical analysis of patient-reported outcomes in lung cancer clinical trials approved between January, 2008, and December, 2017. Lancet Oncol. 2019;20:e582–e589. doi: 10.1016/S1470-2045(19)30335-3.

12. Gloy V., Schmitt A.M., Düblin P., et al. The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020. Int J Cancer. 2023;152:2474–2484. doi: 10.1002/ijc.34473.

13. Grössmann N., Robausch M., Rothschedl E., Wild C., Simon J. Publicly accessible evidence of health-related quality of life benefits associated with cancer drugs approved by the European Medicines Agency between 2009 and 2015. Eur J Cancer. 2020;129:23–31. doi: 10.1016/j.ejca.2020.01.020.

14. Zhang Y., Naci H., Wagner A.K., et al. Overall survival benefits of cancer drugs approved in China from 2005 to 2020. JAMA Netw Open. 2022;5 doi: 10.1001/jamanetworkopen.2022.25973.

15. Damm K., Roeske N., Jacob C. Health-related quality of life questionnaires in lung cancer trials: a systematic literature review. Health Econ Rev. 2013;3:15. doi: 10.1186/2191-1991-3-15.

16. Coens C., Pe M., Dueck A.C., et al. International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL Consortium. Lancet Oncol. 2020;21:e83–e96. doi: 10.1016/S1470-2045(19)30790-9.

17. Oosting S.F., Barriuso J., Bottomley A., et al. Methodological and reporting standards for quality-of-life data eligible for European society for medical oncology-magnitude of clinical benefit scale (ESMO-MCBS) credit. Ann Oncol. 2023;34:431–439. doi: 10.1016/j.annonc.2022.12.004.

18. Schandelmaier S., Conen K., von Elm E., et al. Planning and reporting of quality-of-life outcomes in cancer trials. Ann Oncol. 2015;26:1966–1973. doi: 10.1093/annonc/mdv283.

19. Marandino L., Trastu F., Ghisoni E., et al. Time trends in health-related quality of life assessment and reporting within publications of oncology randomised phase III trials: a meta-research study. BMJ Oncol. 2023;2 doi: 10.1136/bmjonc-2022-000021.

20. Pe M., Dorme L., Coens C., et al. Statistical analysis of patient-reported outcome data in randomised controlled trials of locally advanced and metastatic breast cancer: a systematic review. Lancet Oncol. 2018;19:e459–e469. doi: 10.1016/S1470-2045(18)30418-2.

21. Bouazza Y.B., Chiairi I., El Kharbouchi O., et al. Patient-reported outcome measures (PROMs) in the management of lung cancer: a systematic review. Lung Cancer. 2017;113:140–151. doi: 10.1016/j.lungcan.2017.09.011.

22. Center for Drug Evaluation, National Medical Products Administration Guiding principles for the application of patient-reported outcomes in drug clinical development. https://www.cde.org.cn/main/news/viewInfoCommon/c2f79c22e8678241b030c71523eb300c

23. Gnanasakthy A., Levy C., Norcross L., Doward L., Winnette R. A review of labeling based on patient-reported outcome endpoints for new oncology drugs approved by the European medicines agency (2017-2021) Value Health. 2023;26:893–901. doi: 10.1016/j.jval.2023.01.017.

24. Bonnetain F., Borg C., Adams R.R., et al. How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials. Ann Oncol. 2017;28:2077–2085. doi: 10.1093/annonc/mdx191.

25. Meropol N.J., Egleston B.L., Buzaglo J.S., et al. Cancer patient preferences for quality and length of life. Cancer. 2008;113:3459–3466. doi: 10.1002/cncr.23968.

26. Mierzynska J., Piccinin C., Pe M., et al. Prognostic value of patient-reported outcomes from international randomised clinical trials on cancer: a systematic review. Lancet Oncol. 2019;20:e685–e698. doi: 10.1016/S1470-2045(19)30656-4.

27. Carrillo J.F., Carrillo L.C., Ramirez-Ortega M.C., Ochoa-Carrillo F.J., Oñate-Ocaña L.F. The impact of treatment on quality of life of patients with head and neck cancer and its association with prognosis. Eur J Surg Oncol. 2016;42:1614–1621. doi: 10.1016/j.ejso.2016.05.037.

28. Deng Y., Tu H., Pierzynski J.A., et al. Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma. Eur J Cancer. 2018;92:20–32. doi: 10.1016/j.ejca.2017.12.023.

29. Silvestri G., Pritchard R., Welch H.G. Preferences for chemotherapy in patients with advanced non-small cell lung cancer: descriptive study based on scripted interviews. BMJ. 1998;317:771–775. doi: 10.1136/bmj.317.7161.771.

30. Salas-Vega S., Iliopoulos O., Mossialos E. Assessment of overall survival, quality of life, and safety benefits associated with new cancer medicines. JAMA Oncol. 2017;3:382–390. doi: 10.1001/jamaoncol.2016.4166.

31. Bujosa A., Moltó C., Hwang T.J., et al. Associations with definitive outcomes and clinical benefit of cancer drugs at the time of marketing approval and in the postmarketing period. J Natl Compr Cancer Netw. 2021;1–9 doi: 10.6004/jnccn.2021.7003.

32. Crosby R.D., Kolotkin R.L., Williams G.R. Defining clinically meaningful change in health-related quality of life. J Clin Epidemiol. 2003;56:395–407. doi: 10.1016/s0895-4356(03)00044-1.

33. Chakraborty R., Cannella L., Cottone F., Efficace F. Quality of patient-reported outcome reporting in randomised controlled trials of haematological malignancies according to international quality standards: a systematic review. Lancet Haematol. 2020;7:e892–e901. doi: 10.1016/S2352-3026(20)30292-1.

34. Safa H., Tamil M., Spiess P.E., et al. Patient-reported outcomes in clinical trials leading to cancer immunotherapy drug approvals from 2011 to 2018: a systematic review. J Natl Cancer Inst. 2021;113:532–542. doi: 10.1093/jnci/djaa174.

35. Dunlop E., Ferguson A., Mueller T., et al. What matters to patients and clinicians when discussing the impact of cancer medicines on health-related quality of life? Consensus-based mixed methods approach in prostate cancer. Support Care Cancer. 2022;30:3141–3150. doi: 10.1007/s00520-021-06724-6.

36. Davis C., Naci H., Gurpinar E., Poplavska E., Pinto A., Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ. 2017;359 doi: 10.1136/bmj.j4530.

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