Recommendations to address respondent burden associated with patient-reported outcome assessment.

Patient-reported outcomes (PROs) are increasingly used in healthcare research to provide evidence of the benefits and risks of interventions from the patient perspective and to inform regulatory decisions and health policy. The use of PROs in clinical practice can facilitate symptom monitoring, tailor care to individual needs, aid clinical decision-making and inform value-based healthcare initiatives. Despite their benefits, there are concerns that the potential burden on respondents may reduce their willingness to complete PROs, with potential impact on the completeness and quality of the data for decision-making. We therefore conducted an initial literature review to generate a list of candidate recommendations aimed at reducing respondent burden. This was followed by a two-stage Delphi survey by an international multi-stakeholder group. A consensus meeting was held to finalize the recommendations. The final consensus statement includes 19 recommendations to address PRO respondent burden in healthcare research and clinical practice. If implemented, these recommendations may reduce PRO respondent burden.

Patient-reported frailty phenotype (PRFP) vs. International Myeloma Working Group frailty index (IMWG FI) proxy: A comparison between two approaches to measuring frailty.

INTRODUCTION: Frailty assessments may help to identify patients at highest risk for treatment-related toxicity, early treatment discontinuation due to toxicity, and death in Multiple Myeloma. We aimed to compare the patient-reported frailty phenotype (PRFP) and a modified version of the International Myeloma Working Group frailty index (IMWG FI) in terms of their strengths, limitations, and classification of frailty in a cohort of patients with relapsed/refractory multiple myeloma (RRMM). MATERIALS AND METHODS: Data were pooled from six RRMM Phase 3 randomized clinical trials submitted to the Food and Drug Administration for regulatory review between 2010 and 2021. Patients were classified as fit, intermediate fit/pre-frail, or frail using both PRFP and the IMWG FI proxy. Agreement between the two approaches in classification of patient frailty was assessed using weighted Cohen's kappa. A contingency table and Venn diagram were generated to analyze overlap in categorization of patient frailty across the different severity groups. Descriptive statistics were used to summarize and compare the clinical and demographic characteristics of patients categorized as frail by PRFP vs. IMWG FI proxy. RESULTS: Of the 2,750 patients included in this analysis, IMWG FI proxy classified 16.4% (452) patients as frail, 28.1% (772) as intermediate fit/pre-frail, and 55.5% (1,526) as fit. Meanwhile, PRFP classified 21.7% (597) of patients as frail, 24.5% (675) as intermediate fit/pre-frail, and 53.8% (1478) as fit. Fair agreement was observed between PRFP and IMWG FI proxy (weighted Cohen's Kappa = 0.34 [0.31-0.37]). On average, patients who were categorized as frail by IMWG FI proxy were older and had higher Charlson Comorbidity Index scores than patients classified as frail by PRFP. In contrast, patients who were classified as frail by PRFP had worse EORTC QLQ-C30 Physical Functioning subscale summary scores as compared to patients in the IMWG FI proxy frail group (median score of 40 vs. 47 out of 100). DISCUSSION: Our analysis found fair concordance between IMWG FI proxy and PRFP. This demonstrates that while both frailty models measure the same underlying construct, the variables that constitute each approach may result in differing frailty categorizations for the same patient. Further prospective studies are needed to establish and compare the predictive and prognostic abilities of the different frailty indices in MM.

Initial Steps in Creating a Patient-Centric Addendum to Clinical Trial Informed Consent Forms.

Introduction: The purpose of the informed consent form (ICF) is to outline the risks and benefits of an interventional clinical trial to potential participants. The aim of this study was to explore the feasibility of a short addendum to the ICF, summarizing key points most relevant to potential participants. Methods: A sample of 20 ICFs was reviewed against the requirements of the U.S. federal regulation documents and assessed for readability. Alongside the ICF review, we conducted focus groups and one-on-one interviews with people with lung cancer (n = 9) to learn what information was most important when considering participation in a clinical trial using a hypothetical phase 3 ICF. Results: The 20 ICFs reviewed were from phases 1 to 3, expanded-access, and single-patient trials covering predominantly NSCLC; 60% were global. The mean length of the ICFs was 21 (range: 15-34) pages. The average reading level was tenth grade whereas the average U.S. reading level was eighth grade. Readability varied by section, the "purpose of the study" section had the highest reading level. In the qualitative research component, participants were "overwhelmed" by the hypothetical ICF. Participants were also asked to list information for the addendum; their suggestions broadly map to federal regulations. An addendum with reference to sections in the ICF for additional details was well received. Conclusions: The variations in ICF architecture and readability make it difficult for patients to make an informed decision to participate in a clinical trial. Implications extend beyond lung cancer, highlighting key areas for ICF improvements and providing a roadmap for developing a patient-centric addendum.

Patient Report on the Impact of Coronavirus Disease 2019 and Living With Lung Cancer.

Introduction: Several studies have highlighted coronavirus disease 2019 (COVID-19)-related disruptions in treatment and care in people living with lung cancer. However, few studies have assessed patient-reported perspectives on treatment disruption. This study aims to report the patient perspectives on the impact of COVID-19, vaccination access, and coverage on people living with lung cancer. Methods: Data are from a larger online longitudinal study being run by a lung cancer nonprofit organization, LUNGevity Foundation. The survey is open to all patients living with lung cancer and their caregivers. These analyses focus on data captured in the COVID-19 module and the vaccine questionnaire. Descriptive statistics were computed for categorical and ordinal variables. Results: Overall, 164 people living with lung cancer completed the COVID-19 module. Of these, 54% reported disruption in access to treatment, appointments, participating in research and clinical trials. Participants living with stage IV disease were likely to be more concerned about COVID-19 (35%) compared with those with stage I, II, and III. More than half (66%) had tested for COVID-19 of this group 88% tested negative. There was a correlation among participants testing positive for COVID-19 and the number of household members who also tested positive for COVID-19. In the sample who completed the vaccine survey, almost all (98%) were vaccinated against COVID-19. When a recommendation came from a health care professional, an oncologist was the most likely referral source (33%). Conclusions: An integrative patient-reported view on the impact of COVID-19 is important for adequate preparation to ensure undisrupted treatment and allocation of resources.

Perspectives on Patient-Reported Outcome Data After Treatment Discontinuation in Cancer Clinical Trials.

OBJECTIVES: Patient-reported outcome (PRO) data are critical in understanding treatments from the patient perspective in cancer clinical trials. The potential benefits and methodological approaches to the collection of PRO data after treatment discontinuation (eg, because of progressive disease or unacceptable drug toxicity) are less clear. The purpose of this article is to describe the Food and Drug Administration's Oncology Center of Excellence and the Critical Path Institute cosponsored 2-hour virtual roundtable, held in 2020, to discuss this specific issue. METHODS: We summarize key points from this discussion with 16 stakeholders representing academia, clinical practice, patients, international regulatory agencies, health technology assessment bodies/payers, industry, and PRO instrument development. RESULTS: Stakeholders recognized that any PRO data collection after treatment discontinuation should have clearly defined objectives to ensure that data can be analyzed and reported. CONCLUSIONS: Data collection after discontinuation without a justification for its use wastes patients' time and effort and is unethical.

Measuring Frailty Using Patient-Reported Outcomes (PRO) Data: A Feasibility Study in Patients with Multiple Myeloma.

PURPOSE: The objective of this retrospective study was to determine the feasibility of measuring frailty using patient responses to relevant EORTC QLQ-C30 items as proxy criteria for the Fried Frailty Phenotype, in a cohort of patients with Relapsed/Refractory Multiple Myeloma (RRMM). METHODS: Data were pooled from nine Phase III randomized clinical trials submitted to the FDA for regulatory review between 2010 and 2021, for the treatment of RRMM. Baseline EORTC QLQ-C30 responses were used to derive a patient-reported frailty phenotype (PRFP), based on the Fried definition of frailty. PRFP was assessed for internal consistency reliability, structural validity, and known groups validity. RESULTS: This study demonstrated the feasibility of adapting patient responses to relevant EORTC QLQ-C30 items to serve as proxy Fried frailty criteria. Selected items were well correlated with one another and PRFP as a whole demonstrated adequate internal consistency reliability and structural validity. Known groups analysis demonstrated that PRFP could be used to detect distinct comorbidity levels and distinguish between different functional profiles, with frail patients reporting more difficulty in walking about, washing/dressing, and doing usual activities, as compared to their pre-frail and fit counterparts. Among the 4928 patients included in this study, PRFP classified 2729 (55.4%) patients as fit, 1209 (24.5%) as pre-frail, and 990 (20.1%) as frail. CONCLUSION: Constructing a frailty scale from existing PRO items commonly collected in cancer trials may be a patient-centric and practical approach to measuring frailty. Additional psychometric evaluation and research is warranted to further explore the utility of such an approach.

Best Practice Recommendations for Electronic Patient-Reported Outcome Dataset Structure and Standardization to Support Drug Development.

The electronic patient-reported outcome (ePRO) Dataset Structure and Standardization Project is a multistakeholder initiative formed by Critical Path Institute's PRO Consortium and Electronic Clinical Outcome Assessment (eCOA) Consortium to address issues related to ePRO dataset structure and standardization and to provide best practice recommendations for clinical trial sponsors and eCOA providers. Given the many benefits of utilizing electronic modes to capture PRO data, clinical trials are increasingly using these methods, yet there are challenges to using data generated by eCOA systems. Clinical Data Interchange Standards Consortium (CDISC) standards are used in clinical trials to ensure consistency in data collection, tabulation, and analysis and to facilitate regulatory submission. Currently, ePRO data are not required to follow a standard model, and the data models used often vary by eCOA provider and sponsor. This lack of consistency creates risks for programming and analysis and difficulties for analytics functions generating the required analysis and submission datasets. There is a disconnect between data standards used for study data submission and those used for data collection via case report forms and ePRO forms, which would be mitigated through the application of CDISC standards for ePRO data capture and transfer. The project was formed to collate and examine the issues arising from the lack of adoption of standardized approaches and this paper details recommendations to address those issues. Recommendations to address issues with ePRO dataset structure and standardization include adopting CDISC standards in the ePRO data platform, timely involvement of key stakeholders, ensuring ePRO controls are implemented, addressing issues of missing data early in development, ensuring quality control and validation of ePRO datasets, and use of read-only datasets.

Recommendations on the use of item libraries for patient-reported outcome measurement in oncology trials: findings from an international, multidisciplinary working group.

The use of item libraries for patient-reported outcome (PRO) measurement in oncology allows for the customisation of PRO assessment to measure key health-related quality of life concepts of relevance to the target population and intervention. However, no high-level recommendations exist to guide users on the design and implementation of these customised PRO measures (item lists) across different PRO measurement systems. To address this issue, a working group was set up, including international stakeholders (academic, independent, industry, health technology assessment, regulatory, and patient advocacy), with the goal of creating recommendations for the use of item libraries in oncology trials. A scoping review was carried out to identify relevant publications and highlight any gaps. Stakeholders commented on the available guidance for each research question, proposed recommendations on how to address gaps in the literature, and came to an agreement using discussion-based methods. Nine primary research questions were identified that formed the scope and structure of the recommendations on how to select items and implement item lists created from item libraries. These recommendations address methods to drive item selection, plan the structure and analysis of item lists, and facilitate their use in conjunction with other measures. The findings resulted in high-level, instrument-agnostic recommendations on the use of item-library-derived item lists in oncology trials.

Timing is everything: The importance of patient-reported outcome assessment frequency when characterizing symptomatic adverse events.

OBJECTIVE: Although patient-reported symptoms and side effects are increasingly measured in cancer clinical trials, an appropriate assessment frequency has not yet been established. To determine whether differences in assessment frequency affect the apparent incidence and severity of patient-reported symptoms using two well-established patient-reported outcome measures used within the same clinical trial. METHODS: We examined patient-reported outcome results from AURA3 (NCT02151981), a randomized open-label study comparing Tagrisso (osimertinib) with platinum-based chemotherapy in patients with previously treated estimated glomerular filtration rate/T790M mutation-positive metastatic non-small cell lung cancer. The outcome of interest was the proportion of patients in each arm that reported worsening of nausea, vomiting, fatigue, diarrhea, constipation, and appetite loss from baseline measured using the patient-reported outcome-common terminology criteria for adverse event (weekly) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (every 6 weeks). RESULTS: Similar trends were observed for all six symptoms investigated. Using nausea in the chemotherapy arm as an example, 76% of patients reported any worsening from baseline based on weekly patient-reported outcome-common terminology criteria for adverse event assessments. When using an every 6-week assessment of Quality of Life Questionnaire Core 30 nausea and restricting analysis to an every 6-week assessment for patient-reported outcome-common terminology criteria for adverse event nausea, the proportion of chemotherapy arm patients reporting any worsening of nausea was 40% for both measures. Across the six patient-reported symptomatic adverse events, we observed differential proportions when comparing frequent versus sparse assessment. CONCLUSION: This analysis demonstrates that more frequent assessment of patient-reported symptomatic adverse events will lead to improved detection, and therefore a more complete understanding of the tolerability of experimental anti-cancer therapies.

Time to deterioration of symptoms or function using patient-reported outcomes in cancer trials.

Time-to-event endpoints for patient-reported outcomes, such as time to deterioration of symptoms or function, are frequently used in cancer clinical trials. Although time-to-deterioration endpoints might seem familiar to cancer researchers for being similar to survival or disease-progression endpoints, there are unique considerations associated with their use. The complexity of time-to-deterioration endpoints should be weighed against the information that they add to the tumour, survival, and safety data used to inform the risks and benefits of an investigational drug. Here we use the estimand framework to show how analytical decisions answer different clinical questions of interest, some of which might be uninformative. Challenges including the consideration of intercurrent events, the difficulty in maintaining adequate completion rates, and considerable patient and trial burden from long-term, serial, patient-reported outcome measurements render time to deterioration a problematic approach for widespread use. For trials in which a comparative benefit in symptoms or function is an objective, an analysis at pre-specified relevant timepoints could be a better approach.

US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer.

OBJECTIVES: Many trials conclude "no clinically meaningful detriment" to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration. METHODS: This study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months. RESULTS: Generally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms. CONCLUSIONS: In trials with moderate to large differences in symptomatic toxicity by arm, reporting "no meaningful difference in functioning and HRQL between arms" based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.

Floor and ceiling effects in the EORTC QLQ-C30 Physical Functioning Subscale among patients with advanced or metastatic breast cancer.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 Physical Functioning subscale is a widely used patient-reported outcome measure that quantifies cancer patients' physical functioning. Strong floor/ceiling effects can affect a scale's sensitivity to change. The aim of this study was to characterize floor/ceiling effects of the physical functioning domain in patients with advanced/metastatic breast cancer enrolled in commercial clinical trials and a community-based trial. METHODS: The clinical trial cohort comprised patients from 5 registrational trials submitted to the Food and Drug Administration for review (2010-2017). The community cohort comprised a subgroup of patients from the Alliance Patient Reported Outcomes to Enhance Cancer Treatment (PRO-TECT) trial. The distribution of patient responses to Physical Functioning items and the summed score were assessed at the baseline and 3-month follow-up for both cohorts. Descriptive statistics were used to determine floor/ceiling effects at the item and scale levels. RESULTS: The clinical trial cohort and the community cohort consisted of 2407 and 178 patients, respectively. Twenty-four percent or more of the respondents reported "not at all" for having trouble/needing help with each Physical Functioning item across both cohorts and measurement time points. Fourteen to twenty percent of the patients scored perfectly (100 of 100) on the Physical Functioning subscale summary measure (where higher scores indicated better physical functioning) across both cohorts and time points. CONCLUSIONS: Minor floor effects and notable ceiling effects were found at the item and scale levels of the Physical Functioning subscale, regardless of cohort, and this creates some uncertainty about its ability to detect changes in physical functioning among high-functioning patients. Investigators may consider adding additional high-functioning items from the EORTC's item library to more accurately describe the impact of anticancer treatment on patients' physical functioning.

Patient-Reported Outcomes in Pediatric Cancer Registration Trials: A US Food and Drug Administration Perspective.

Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration's (FDA's) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional outcomes from the patient's perspective.This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling.We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report.PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute's Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient's perspective, in pediatric oncology trials.

Electronic patient-reported outcomes monitoring during lung cancer chemotherapy: A nested cohort within the PRO-TECT pragmatic trial (AFT-39).

OBJECTIVES: Patients with lung cancer have high symptom burden and diminished quality of life. Electronic patient-reported outcome (PRO) platforms deliver repeated longitudinal surveys via web or telephone to patients and alert clinicians about concerning symptoms. This study aims to determine feasibility of electronic PRO monitoring in lung cancer patients receiving treatment in community settings. METHODS: Adults receiving treatment for advanced or metastatic lung cancer at 26 community sites were invited to participate in a prospective trial of weekly electronic PRO symptom monitoring for 12 months (NCT03249090). Surveys assessing patients' satisfaction with the electronic PRO system were administered at 3 months. Descriptive statistics were generated for demographics, survey completion rates, symptom occurrence, and provider PRO alert management approaches. Pairwise relationships between symptom items were evaluated using intra-individual repeated-measures correlation coefficients. RESULTS: Lung cancer patients (n = 118) participating in electronic PROs were older (mean 64.4 vs 61.9 years, p = 0.03), had worse performance status (p = 0.002), more comorbidities (p = 0.02), and less technology experience than patients with other cancers. Of delivered weekly PRO surveys over 12 months, 91% were completed. Nearly all (97%) patients reported concerning (i.e., severe or worsening) symptoms during participation, with 33% of surveys including concerning symptoms. Pain was the most frequent and longest lasting symptom and was associated with reduced activity level. More than half of alerts to clinicians for concerning symptoms led to intervention. The majority (87%) would recommend using electronic PRO monitoring to other lung cancer patients. CONCLUSIONS: Remote longitudinal weekly monitoring of patients with lung cancer using validated electronic PRO surveys was feasible in a multicenter, community-based pragmatic study. A high symptom burden specific to lung cancer was detected and clinician outreach in response to alerts was frequent, suggesting electronic PROs may be a beneficial strategy for identifying actionable symptoms and allow opportunities to optimize well-being in this population.

Patient-Reported Outcomes After Treatment Discontinuation: Commercial Clinical Trial Data From Four Cancer Types.

OBJECTIVES: How frequently patient-reported outcome (PRO) data are collected in commercial cancer clinical trials after treatment discontinuation and the quality of that data are poorly understood. We reviewed treatment discontinuation follow-up PRO data collection to learn about trials collecting these data and understand data quality. The review included 4 cancer types representing potential for long- (prostate cancer), medium-/long- (breast cancer), and short-term (pancreatic cancer and hepatocellular carcinoma) follow-up owing to disease trajectory. METHODS: We reviewed registration trials in US Food and Drug Administration databases between January 2010 and January 2019. Protocols were reviewed to determine whether PROs were collected and, if so, whether these included the follow-up phase. Clinical study reports were reviewed when follow-up PROs were collected to determine completion rates. Results were summarized using descriptive analyses. RESULTS: Of the 46 trials containing PRO data, 46% had at least 1 follow-up PRO assessment. Follow-up schedules of assessment were wide ranging; the first assessment occurred between 30 days and 6 months after stopping treatment with follow-up for as long as 3 years. PRO completion rates were reported in 57% of 21 trials; at the first follow-up assessment, completion rates for the treatment arm ranged from 38% to 91% and from 41% to 100% in the control arm. CONCLUSIONS: The quality of the follow-up PRO data, based on completion rates, was variable, as was the duration of follow-up. A clear research objective should be developed for follow-up PRO data, accounting for patient burden. If PRO data are collected, monitoring should be implemented to improve completion because poor completion limits data use in the benefit-risk assessment.

Does Knowledge of Treatment Assignment Affect Patient Report of Symptoms, Function, and Health Status? An Evaluation Using Multiple Myeloma Trials.

OBJECTIVES: Unblinded trials are common in oncology, but patient knowledge of treatment assignment may bias response to questionnaires. We sought to ascertain the extent of possible bias arising from patient knowledge of treatment assignment. METHODS: This is a retrospective analysis of data from 2 randomized trials in multiple myeloma, 1 double-blind and 1 open label. We compared changes in patient reports of symptoms, function, and health status from prerandomization (screening) to baseline (pretreatment but postrandomization) across control and investigational arms in the 2 trials. Changes from prerandomization scores at ~2 and 6 months on treatment were evaluated only across control arms to avoid comparisons between 2 different experimental drugs. All scores were on 0- to 100-point scales. Inverse probability weighting, entropy balancing, and multiple imputation using propensity score splines were used to compare score changes across similar groups of patients. RESULTS: Minimal changes from screening were seen at baseline in all arms. In the control arm, mean changes of <7 points were seen for all domains at 2 and 6 months. The effect of unblinding at 6 months in social function was a decline of less than 6 points (weighting: -3.09; 95% confidence interval -8.41 to 2.23; balancing: -4.55; 95% confidence interval -9.86 to 0.76; imputation: -5.34; 95% confidence interval -10.64 to -0.04). CONCLUSION: In this analysis, we did not find evidence to suggest that there was a meaningful differential effect on how patients reported their symptoms, function or health status after knowing their treatment assignment.