Patient-reported Outcomes In Clinical Trials Research Articles

Joint Models Inform the Longitudinal Assessment of Patient-Reported Outcomes in Clinical Trials: A Simulation Study and Secondary Analysis of the Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery (RELIEF) Randomized Controlled Trial

Evaluate the utility of a joint model when analysing a patient-reported endpoint as part of a randomized controlled trial in which censoring occurs when patients die during follow-up. The present study comprises two parts: first we re-analyzed data from a previously published randomized controlled trial comparing two fluid regimens in the first 24 hours of major abdomino-pelvic surgery ('RELIEF' trial). In this trial, patient-reported disability was measured at multiple timepoints before and after surgery. Next, we conducted a simulation study to jointly emulate patient-reported disability and survival, similar to the RELIEF trial, under nine treatment-outcome scenarios. In both parts, we compared a joint model analysis to a linear mixed effect model combined with one of several traditional methods of handling longitudinal missingness: available data analysis, complete case analysis, last observation carried forward, and worst-case assumption. In part one, the joint model revealed no between-group differences in patient-reported disability at one, three, six, and 12 months after surgery. The worst-case approach consistently resulted in the largest deviation from the joint model estimates, although in this particular setting none of the approaches materially changed the study's conclusions. In part two, the simulations revealed that across all treatment-outcome scenarios, the joint model expectedly produced unbiased estimates of patient-reported disability. Similarly, employing an approach based on all available data (i.e., relying on the maximum likelihood estimator for handling missingness) yielded disability estimates close to the simulated values, albeit with slight bias across some scenarios. The last observation carried forward approach mirrored the joint model's estimates except when the treatment had a non-null effect on patient-reported disability. The worst case analysis resulted in high bias, which was particularly evident when the treatment had a large effect on survival. The complete case analysis resulted in high bias across all scenarios. In randomized trials that employ a patient-reported outcome as one of their endpoints, a joint model can address bias arising from informative missingness related to death. Methods for handling missingness based on all available data appear to be a reasonable alternative to joint models, with only slight bias across some simulated scenarios.

A Hearing Intervention and Health-Related Quality of Life in Older Adults

Health-related quality of life is a critical health outcome and a clinically important patient-reported outcome in clinical trials. Hearing loss is associated with poorer health-related quality-of-life in older adults. To investigate the 3-year outcomes of hearing intervention vs health education control on health-related quality of life. This secondary analysis of a randomized clinical trial included participants treated for hearing loss at multiple US centers between 2018 and 2019 with 3-year follow-up completed in 2022. Eligible participants were aged 70 to 84 years, had untreated hearing loss, and were without substantial cognitive impairment. Participants were randomized (1:1) to hearing intervention or health education control and followed every 6 months. Hearing intervention (provision of hearing aids and related technologies, counseling, education) or health education control (individual sessions covering topics relevant to chronic disease, disability prevention). Three-year change in the RAND-36 physical and mental health component scores over 3 years. The 8 individual domains of health-related quality-of-life were additionally assessed. Outcomes measured at baseline and at 6-month, 1-year, 2-year, and 3-year follow-ups. Intervention effect sizes estimated using a 2-level linear mixed effects model under the intention-to-treat principle. A total of 977 participants were analyzed (mean [SD] age, 76.8 [4.0] years; 523 female [53.5%]; 112 Black [11.5%], 858 White [87.8%]; 521 had a Bachelor's degree or higher [53.4%]), with 490 in the hearing intervention and 487 in the control group. Over 3 years, hearing intervention (vs health education control) had no significant association with physical (intervention, -0.49 [95% CI, -3.05 to 2.08]; control, -0.92 [95% CI, -3.39 to 1.55]; difference, 0.43 [95% CI, -0.64 to 1.51]) or mental (intervention, 0.38 [95% CI, -1.58 to 2.34]; control, -0.09 [95% CI, -1.99 to 1.81]; difference, 0.47 [95% CI, -0.41 to 1.35]) health-related quality of life. In this secondary analysis of a randomized clinical trial, hearing intervention had no association with physical and mental health-related quality-of-life over 3 years among older adults with hearing loss. Additional intervention strategies may be needed to modify health-related quality among older adults with hearing loss. ClinicalTrials.gov Identifier: NCT03243422.

Patient-reported outcomes in neuro-oncology.

To provide up-to-date evidence on patient-reported outcomes (PROs) in neuro-oncology, with a focus on the core constructs of health-related quality of life (HRQoL) and the use of PROs in clinical trials and clinical practice.[Supplemental Digital Content: Video Abstract PROs in Neuro-Oncology.mov]. PROs are gaining importance in brain tumor research and medical care. For patients with a brain tumor, core PRO constructs are pain, difficulty communicating, perceived cognition, seizures, symptomatic adverse events, physical functioning and role and social functioning, which are assessed through patient-reported outcome measures (PROMs). Initiatives have been taken to improve the reliability and robustness of PRO data, including standardization of items included in clinical trial protocols (the SPIRIT-PRO extension) and formulation of PRO priority objectives for use in clinical trials (the SISAQOL-Innovative Medicines Initiative). In brain tumor patients with cognitive impairment, caregiver-reported outcomes may complement or replace PROs to increase accuracy. The next key challenge will be to widely implement PROs and apply PRO data in clinical practice to benefit patients with brain tumors. PROs are clinically relevant endpoints providing information only known by the patient. Standardization of the use of PROs in clinical trials and wide implementation in clinical practice is needed to improve HRQoL of brain tumor patients.

Abstract PO3-10-10: Are we adequately integrating patient reported outcomes in breast cancer clinical trials?

Abstract Background: Integrating patient reported outcomes (PROs) in cancer care enhances clinical outcomes and creates a paradigm shift in providing patient-centered care. Several studies performed in the past 15 years have demonstrated that systematic monitoring of patients using PROs through surveys improve patient-clinician communication, clinician awareness of symptoms, symptom management, patient satisfaction, quality of life, and overall survival. There has been uncertainty over the type of PRO system to implement in cancer care, how to evaluate PRO in clinical trials, and how to compare this to the clinician common terminology criteria for adverse events (CTCAE). The PRO concept was first introduced in 1975 with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) survey. In May 2018, the National Cancer Institute established the PRO-CTCAE to be utilized for cancer patients to report and grade their treatment related adverse events, like that of clinician reported CTCAE. The goal of our study was to evaluate frequency of PRO incorporation in phase III breast cancer clinical trials. Methods: New England Journal of Medicine, Journal of Clinical Oncology, and Lancet were systematically searched to identify phase III breast cancer clinical trials published between January 2018 and June 2023. A total of 113 phase III studies were identified, 87 of which had reported protocols. Studies that did not demonstrate protocols on these search engines were not included in the review. Of these 87 clinical trials, 36 studies documented evaluation of PRO. These studies were segregated by year of publication. For each year, the number of total phase III breast cancer clinical trials that were published were compared to those that were published and evaluated PRO. A percentage was generated and allowed for a longitudinal trend to be analyzed over a 5-year period to assess if there was improved frequency of PRO integration into breast cancer clinical trials. Summary statistics were calculated using SAS 9.4. Results: 36 of 113 trials demonstrated PRO use and 26 utilized EORTC-QoL, 1 used PRO-CTCAE, and 9 used another measure of PRO assessment within their study protocol (such as FACT-B and PHQ-9. Additionally, in 2018, 33% of published breast cancer studies included PRO data. Since then, there have been fluctuations in breast cancer studies collecting PRO; 2019: 33%, 2020: 47%, 2021: 43%, 2022: 73%, and since the start of 2023: 9%. Conclusions: Our data suggests a trend towards improvement in frequency of PRO data collection in breast cancer clinical trials over the past 5 years, exemplified by the marked increase in 2022. There remains a need to incorporate PROs in clinical trials and routine care to improve patient experience and provide patient-centered care. Citation Format: Yadav Rina, Zhengyan Huang, Jessica Moss, Garima Gupta. Are we adequately integrating patient reported outcomes in breast cancer clinical trials? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-10-10.

Health-related quality of life : Concept, measurement and fields of application

Health-related quality of life (HRQoL) is the most important patient-reported outcome in clinical trials and patient care. HRQoL is further considered as target variable in treatment guidelines and as outcome indicator in the evaluation of the quality of care. Numerous validated questionnaires are available for the assessment of HRQoL from the perspective of patients with skin diseases. However, many are of inadequate methodological quality, indicating the need for further research in the development of high-quality measurement instruments. The implementation of routine electronic HRQoL assessments is apromising approach.

Critical Comments by Food and Drug Administration Reviewers on Patient-Reported Outcomes in Food and Drug Administration Regulatory Submissions (2018-2021)

ObjectivesThis article examined the inclusion of patient-reported outcome (PRO) data in new drug applications (NDAs) submitted to the Food and Drug Administration (FDA) and approved from 2018 to 2021. The importance of assessing PROs, which capture patients’ perspectives on the disease and treatment experience, has been underscored by many stakeholders, including regulatory authorities. Despite the increasing inclusion of PRO assessments in registration trials, inclusion of language related to PRO results in approved product labeling varies widely. MethodsThis study examined FDA submission packages for NDAs approved by the FDA from 2018 to 2021 to identify critical reviewer comments related to PROs. Comments were identified and categorized by the type of criticism. Reviewers considered both oncology and nononcology indications. ResultsAssessment of PROs was included in 66.2% of the 210 submissions reviewed. Critical comments were identified in 45.3% of these applications; comments most commonly related to statistical analysis considerations, fit for purpose, and study design. Other categories of critical comment included data quality, lack of treatment benefit, administrative considerations, and miscellaneous issues. Differences were observed between oncology and nononcology NDAs with regard to the number and type of comments included in each of these categories. The findings highlight the importance of planning statistical analyses, establishing content validity, carefully considering study design, maximizing data quality, and demonstrating treatment benefit, among other issues. ConclusionsOverall, this study offers insight into the landscape of PRO data included in recently approved NDAs, along with recommendations for improving the quality and reporting of PROs in clinical trials.

15 years of patient-reported outcomes in clinical trials leading to GU cancer drug approvals: a systematic review on the quality of data reporting and analysis

Standardized, high-quality PRO data reporting is crucial for patient centered care in the field of oncology, especially in clinical trials that establish standard of care. This study evaluated PRO endpoint design, conduct and reporting methods in FDA approved drugs for GU malignancies. A systematic review of the FDA archives identified GU cancer drug approvals from Feb 2007 to July 2022. ClinicalTrials.gov and PubMed were used to retrieve relevant data. PRO data was screened, and analytic tools, interpretation methods in the published papers and study protocols were reviewed. Compliance with PRO reporting standards were assessed using PRO Endpoint Analysis Score (PROEAS), a 24-point scoring scale from Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium (SISAQOL). We assessed 40 trial protocols with 27,011 participants, resulting in 14 renal cell cancer (RCC), 16 prostate cancer (PC), and 10 urothelial cancer (UC) approvals. PRO data was published for 27 trials, with 23 PRO publications (85%) focusing solely on PRO data, while 4 (15%) included PRO data in the original paper. Median time between primary clinical and secondary paper with PRO data was 10.5 months (range: 9-25 months). PROs were not planned as primary endpoints for any study but 14 (52%) reported them as secondary, 10 (37%) as exploratory outcomes, and 3 (11%) lacked any clarity on PRO data as endpoint. Mean PROEAS score of all GU cancers was 11.10 (range: 6-15), RCC (11.86, range: 6-15), UC (11.50, range: 9-14), and PC (10.56, range: 6-15). None metall the SISAQOL recommendations. Low overall PROEAS score and delays in PRO data publication in GU cancer drug trials conducted in the past decade emphasize the need for improvement in quality of design and conduct of PRO endpoint in future trials and accelerated publication of PRO endpoints, using standardized analysis, and prespecified hypothesis driven endpoint. These improvements are essential for facilitating interpretation and application of PRO study findings to define patient care. None.

Maintenance Treatment for Metastatic Pancreatic Cancer: Balancing Therapeutic Intensity with Tolerable Toxicity.

Metastatic pancreatic ductal adenocarcinoma is typically treated with multi-agent chemotherapy until disease progression or intolerable cumulative toxicity. For patients whose disease shows ongoing control or response beyond a certain timeframe (≥3-4 months), options include pausing chemotherapy with close monitoring or de-escalating to maintenance therapy with the goal of prolonging progression-free and overall survival while preserving quality of life. There is currently no universally accepted standard of care and a relative dearth of randomized clinical trials in the maintenance setting. Conceptually, such therapy can entail continuing the least toxic components of a first-line regimen and/or introducing novel agent(s) such as the poly(ADP-ribose) polymerase inhibitor olaparib, which is presently the only approved drug for maintenance treatment and is limited to a genetically defined subset of patients. In addition to identifying new therapeutic candidates and combinations in the maintenance setting, including targeted agents and immunotherapies, future research should focus on better understanding this unique biologic niche and how treatment in the maintenance setting may be distinct from resistant/refractory disease; identifying molecular predictors for more effective pairing of specific treatments with patients most likely to benefit; and establishing patient-reported outcomes in clinical trials to ensure accurate capture of quality of life metrics.

Systematic Review of Use of Patient-Reported Outcomes in Interventional Radiology

IntroductionA patient-reported outcome (PRO) is any outcome reported directly by the patient, in contradistinction to a clinician-reported outcomes, which have dominated clinical research. This systematic review evaluates the ways in which PROs have been used in the interventional radiology literature. MethodsSystematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was designed and conducted by a medical librarian. Studies were screened for inclusion by two independent members, with a third member as a conflict resolver. The data were extracted from each study in a consistent and structured manner. ResultsIn all, 354 studies met criteria for full-text analysis; 218 of 354 (62%) used a prospective design and most frequently provided level III (249 of 354, 70%) or level I (68 of 354, 19%) evidence. The manner in which PROs were obtained was reported in 125 of 354 (35%) of studies. Questionnaire response rate was documented in 51 of 354 (14%) studies, and questionnaire completion rate was documented in 49 of 354 (14%) studies. Of 354 studies, 281 (79%) studies used at least one independently validated questionnaire. The disease domains most commonly assessed via PRO were women’s health (62 of 354, 18%) and men’s health (60 of 354, 17%). DiscussionWider development, validation, and systematic use of PROs in IR would enable more informed patient-centered decision making. A greater focus on PROs in clinical trials would elucidate expected outcomes from the patient’s perspective, simplifying comparisons with therapeutic alternatives. To produce more convincing evidence, trials must apply validated PROs rigorously and report possible confounding factors consistently.

PCR54 A Systematic Review and Quality Assessment of Cardiovascular Disease-Specific Patient Reported Outcome Measures (PROMS): Part II Psychometric Properties

Health-related Quality of Life (HRQoL) instruments for cardiovascular diseases (CVDs) have been commonly used to measure important patient-reported outcomes in clinical trials and practices. This study aimed at systematically identifying and evaluating the psychometric properties of CVD-specific HRQoL instruments.

A cross-sectional study on the application of patient-reported outcome measurements in clinical trials of traditional Chinese medicine in mainland China.

Objectives: Patient-reported outcomes (PROs) provide a global perspective of patient health status which plays an enormous role in evaluating clinical efficacy. However, the application of PROs in traditional Chinese medicine (TCM) was still insufficiently studied in mainland China. Methods: This cross-sectional study was performed based on interventional clinical trials of TCM that were conducted in mainland China from 1 January 2010, to 15 July 2022. Data was retrieved from the ClinicalTrials.gov and Chinese Clinical Trial Registry. We included interventional clinical trials of TCM for which the country of the primary sponsors or recruitment settings in mainland China. For each included trial, data including clinical trial phases, study settings, participant's age, sex, diseases, and the patient-reported outcome measures (PROMs) were extracted. Trials were categorized into four categories according to 1) listed PROs as primary endpoints, 2) listed PROs as secondary endpoints, 3) listed PROs as coprimary outcomes (both primary and secondary endpoints), and 4) did not mention any PROMs. Results: Among a total of 3,797 trials, 680 (17.9%) trials listed PROs as primary endpoints, 692 (18.2%) trials listed PROs as secondary endpoints, and 760 (20.0%) trials listed PROs as coprimary endpoints. Among 675,787 participants included in the registered trials, 448,359 (66.3%) patients' data were scientifically collected by PRO instruments. Neurological diseases (11.8%), musculoskeletal symptoms (11.5%), mental health conditions (9.1%) were the most common conditions evaluated by PROMs. Disease-specific symptoms related concepts were used most frequently (51.3%), followed by health-related quality of life concepts. Visual analog scale, 36-item Short-Form Health Questionnaire, and TCM symptom score were the most common PROMs in these trials. Conclusion: In this cross-sectional study, the use of PROs increased in the past decades according to clinical trials of TCM conducted in mainland China. Considering that the application of PROs in clinical trials of TCM has some existing issues including uneven distribution and lack of normalized PROs of TCM, further study should be focused on the standardization and normalization of TCM-specific scales.

A comparison of the efficacy of Skindex-16 and Skindex-29 in dermatomyositis.

Recently, more emphasis has been placed on patient-reported outcomes in clinical trials, which has inadvertently led to an increase in respondent burden. In this study, we found that the Skindex-16 form captures patient-reported quality of life in dermatomyositis as well as the Skindex-29 form but with fewer questions. Additional questions regarding photosensitivity, body image and cosmetic use did not correlate with skin activity in dermatomyositis.

Role of Patient-Reported Outcomes in Clinical Trials in Metastatic Colorectal Cancer: A Scoping Review

To perform a scoping review on the use of Patient-Reported Outcome Measures (PROMs) in randomized trials on systemic therapy in patients with metastatic colorectal cancer (mCRC) between 2010 and 2021. First, a search on clinicaltrials.gov was performed, looking for randomized trials in mCRC. The use of PROMs was analyzed quantitatively. Subsequently, we assessed the completeness of PROM reporting based on the CONSORT PRO extension in publications related to the selected trials acquired using Embase and PubMed. A total of 46/176 trials were registered on clinicaltrials.gov used PROMs. All these trials used validated PROM instruments. The EORTC QLQ-C30 was most frequently used (37 times), followed by the EQ-5D (21 times) and the EORTC QLQ-CR29 (six times). A total of 56/176 registered trials were published. In 35% (n = 20), the results of the PROMs were available. Overall, 7/20 (35%) trials documented all items of the CONSORT PRO extension and quality of reporting according to the CONSORT PRO extension was higher than in the period 2004-2012. In 3/20 (15%) of the published trials, the results of PROMs were not discussed nor included in the positioning of the new treatment compared to the reference treatment. When PROMs are used, the quality of reporting on patient-reported outcomes is improving, but this must continue in order to optimize the translation of trial results to individual patient values.

Socioeconomic deprivation and patient-reported outcomes in symptom management trials for patients with breast cancer.

158 Background: Patient-reported outcomes (PROs) provide important metrics to guide treatment decision making and have been shown to be predictive of clinical outcomes. Neighborhood socioeconomic deprivation, characterized by lower levels of income, education, and housing quality, has been shown to be associated with worse outcomes in clinical trials. However, the relationship between deprivation and PROs in clinical trials has not been systematically examined. Methods: We examined the relationship between multiple PRO domains and deprivation using data from 3 randomized trials (S0927, S1200, S1202) of interventions for aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) among female breast cancer patients. The studies were conducted by the SWOG Cancer Research Network. Deprivation was measured using patients’ residential zip code linked to the area deprivation index (ADI), measured on a 0-100 scale and categorized into tertiles based on national ADI distribution. Multivariable linear regression was used with adjustment for patient age, race, ethnicity, cancer stage, days on AI, and body mass index (BMI). Secondary models adjusted for rurality and insurance (Medicaid/no insurance v. private/Medicare). Average joint pain and pain interference (each on 0-10 scales) based on the Brief Pain Inventory, and physical and functional wellbeing (PWB, FWB) based on the FACT-ES (on 0-28 scales), at baseline were analyzed. Results: Overall, 761 patients were examined. Median age was 60 years, 8% of patients were Black, 5.5% were Hispanic, 87% had Stage I or II disease, and median duration on AI was 365 days. 51% of patients were from least deprived areas (bottom tertile of ADI), while 15% were from the most deprived areas (top tertile). Compared with patients from the least deprived areas, patients in the most deprived areas had worse FWB (β = -1.53, 95% CI: -2.7, -0.4; p =.01) and average pain scores (β = 0.51, 95% CI: 02, 0.8; p = 0.002) at baseline. Patients from more deprived areas (middle tertile of ADI) had worse FWB (β = -1.3, 95% CI: -2.1, -0.4; p =.005) and pain interference (β = 0.5, 95% CI: 0.2, 0.9; p =.002) compared to those from least deprived areas. For pain outcomes, the ADI coefficient was attenuated but statistically significant with adjustment for insurance. The association of FWB with ADI was not statistically significant after adjusting for insurance. No statistically significant differences were noted for PWB. Conclusions: Patients with AIMSS who live in neighborhoods with higher social needs had slightly worse FWB joint pain, and pain interference at baseline, but similar PWB. The effect of insurance on the PRO-ADI association indicates that individual access to healthcare explains some of the area-level differences in PROs. Future work will examine differences in PRO trajectory by ADI, adjusted for insurance, over the course of patient participation in these trials.

Use and Reporting of Patient-Reported Outcomes in Trials of Palliative Radiotherapy

Approximately 50% of all patients with cancer have an indication for radiotherapy, and approximately 50% of radiotherapy is delivered with palliative intent, with the aim of alleviating symptoms. Symptoms are best assessed by patient-reported outcomes (PROs), yet their reliable interpretation requires adequate reporting in publications. To investigate the use and reporting of PROs in clinical trials of palliative radiotherapy. This preregistered systematic review searched PubMed/Medline, EMBASE, and the Cochrane Center Register of Controlled Trials for clinical trials of palliative radiotherapy published from 1990 to 2020. Key eligibility criteria were palliative setting, palliative radiotherapy as treatment modality, and clinical trial design (per National Institutes of Health definition). Two authors independently assessed eligibility. Trial characteristics were extracted and standard of PRO reporting was assessed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. The association of the year of publication with the use of PROs was assessed by logistic regression. Factors associated with higher CONSORT-PRO adherence were analyzed by multiple regression. This study is reported following the PRISMA guidelines. Among 7377 records screened, 225 published clinical trials representing 24 281 patients were eligible. Of these, 45 trials (20%) used a PRO as a primary end point and 71 trials (31%) used a PRO as a secondary end point. The most prevalent PRO measures were the Numeric Rating Scale/Visual Analogue Scale (38 trials), European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (32 trials), and trial-specific unvalidated measures (25 trials). A more recent year of publication was significantly associated with a higher chance of PROs as a secondary end point (odds ratio [OR], 1.04 [95% CI, 1.00-1.07]; P = .03) but not as primary end point. Adherence to CONSORT-PRO was poor or moderate for most items. Mean (SD) adherence to the extension adherence score was 46.2% (19.6%) for trials with PROs as primary end point and 31.8% (19.8%) for trials with PROs as a secondary end point. PROs as a primary end point (regression coefficient, 9.755 [95% CI, 2.270-17.240]; P = .01), brachytherapy as radiotherapy modality (regression coefficient, 16.795 [95% CI, 5.840-27.751]; P = .003), and larger sample size (regression coefficient, 0.028 [95% CI, 0.006-0.049]; P = .01) were significantly associated with better PRO reporting per extension adherence score. In this systematic review of palliative radiotherapy trials, the use and reporting of PROs had room for improvement for future trials, preferably with PROs as a primary end point.

Considerations for Selecting Cognitive Endpoints and Psychological Patient-Reported Outcomes for Clinical Trials in Pediatric Patients With Sickle Cell Disease.

Pediatric patients with sickle cell disease (SCD) experience a range of medical complications that result in significant morbidity and mortality. Recent advances in prophylactic and curative treatment approaches have highlighted the need for sensitive and clinically-meaningful trial endpoints. The detrimental effects of cognitive and psychological difficulties on social and economic mobility are well described. Although numerous reviews have assessed cognitive outcomes in other rare genetic disorders, SCD has not received the same focus. This review describes the cognitive (i.e., executive function and processing speed) and psychological domains (i.e., depression and anxiety) that are consistently associated with SCD pathology and, therefore, may be of particular interest as clinical trial endpoints. We then discuss corresponding well-validated and reliable cognitive tests and patient-reported outcomes (PROs) that may be appropriate for clinical trials given their robust psychometric properties, ease of administration, and previous use in the SCD population. Further, we provide a discussion of potential pitfalls and considerations to guide endpoint selection. In line with the move toward patient-centered medicine, we identify specific tests (e.g., NIH Toolbox Cognition Module, Wechsler Cancellation Test) and psychological PROs (e.g., PROMIS depression and anxiety scales) that are sensitive to SCD morbidity and have the potential to capture changes that are clinically meaningful in the context of patients' day to day lives. In particularly vulnerable cognitive domains, such as executive function, we highlight the advantages of composite over single-test scores within the context of trials. We also identify general (i.e., practice effects, disease heterogeneity) and SCD-specific considerations (i.e., genotype, treatment course, and disease course, including degree of neurologic, pain, and sleep morbidity) for trial measures. Executive function composites hold particular promise as trial endpoints that are clinically meaningful, amenable to change, relatively easy to collect, and can be incorporated into the routine care of patients with SCD in various settings and countries.

The PROTEUS-Trials Consortium: Optimizing the use of patient-reported outcomes in clinical trials.

Background:The assessment of patient-reported outcomes in clinical trials has enormous potential to promote patient-centred care, but for this potential to be realized, the patient-reported outcomes must be captured effectively and communicated clearly. Over the past decade, methodologic tools have been developed to inform the design, analysis, reporting, and interpretation of patient-reported outcome data from clinical trials. We formed the PROTEUS-Trials Consortium (Patient-Reported Outcomes Tools: Engaging Users and Stakeholders) to disseminate and implement these methodologic tools.Methods:PROTEUS-Trials are engaging with patient, clinician, research, and regulatory stakeholders from 27 organizations in the United States, Canada, Australia, the United Kingdom, and Europe to develop both organization-specific and cross-cutting strategies for implementing and disseminating the methodologic tools. Guided by the Knowledge-to-Action framework, we conducted consortium-wide webinars and meetings, as well as individual calls with participating organizations, to develop a workplan, which we are currently executing.Results:Six methodologic tools serve as the foundation for PROTEUS-Trials dissemination and implementation efforts: the Standard Protocol Items: Recommendations for Interventional Trials-patient-reported outcome extension for writing protocols with patient-reported outcomes, the International Society for Quality of Life Research Minimum Standards for selecting a patient-reported outcome measure, Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium recommendations for patient-reported outcome data analysis, the Consolidated Standards for Reporting of Trials-patient-reported outcome extension for reporting clinical trials with patient-reported outcomes, recommendations for the graphic display of patient-reported outcome data, and a Clinician’s Checklist for reading and using an article about patient-reported outcomes. The PROTEUS-Trials website (www.TheProteusConsortium.org) serves as a central repository for the methodologic tools and associated resources. To date, we have developed (1) a roadmap to visually display where each of the six methodologic tools applies along the clinical trial trajectory, (2) web tutorials that provide guidance on the methodologic tools at different levels of detail, (3) checklists to provide brief summaries of each tool’s recommendations, (4) a handbook to provide a self-guided approach to learning about the tools and recommendations, and (5) publications that address key topics related to patient-reported outcomes in clinical trials. We are also conducting organization-specific activities, including meetings, presentations, workshops, and webinars to publicize the existence of the methodologic tools and the PROTEUS-Trials resources. Work to develop communications strategies to ensure that PROTEUS-Trials reach key audiences with relevant information about patient-reported outcomes in clinical trials and PROTEUS-Trials is ongoing.Discussion:The PROTEUS-Trials Consortium aims to help researchers generate patient-reported outcome data from clinical trials to (1) enable investigators, regulators, and policy-makers to take the patient perspective into account when conducting research and making decisions; (2) help patients understand treatment options and make treatment decisions; and (3) inform clinicians’ discussions with patients regarding treatment options. In these ways, the PROTEUS Consortium promotes patient-centred research and care.

Endpoints in Heart Failure Drug Development.

Heart failure (HF) is a major health problem worldwide. The development of effective drug and/or device therapy is crucial to mitigate the significant morbidity, mortality and healthcare costs associated with HF. The choice of endpoint in clinical trials has important practical and clinical implications. Outcomes of interest including mortality and HF hospitalisations provide robust evidence for regulatory approval granted there is sufficiency of safety data. At the same time, it is important to recognise that HF patients experience significant impairments in functional capacity and quality of life, underscoring the need to incorporate parameters of symptoms and patient-reported outcomes in clinical trials. In this review, the authors summarise the evolution and definition of cardiovascular endpoints used in clinical trials, discuss approaches to study design to allow the incorporation of mortality, morbidity and functional endpoints and, finally, examine the current challenges and suggest steps for the development of cardiovascular endpoints that are effective, meaningful and meet the needs of all relevant stakeholders, including patients, physicians regulators and sponsors.

Treatment Outcomes Associated With Dupilumab Use in Patients With Atopic Dermatitis

Clinical trial populations may not reflect clinical practice: knowledge generated in other settings can inform clinical decision-making. To evaluate self-reported disease control and quality of life after initiating dupilumab treatment in patients with atopic dermatitis (AD) in the the clinical setting. This cohort study using an online survey administered prior to (baseline) and at 1, 2, 3, 6, 9, and 12 months after dupilumab initiation included adults with moderate-to-severe AD who initiated treatment with dupilumab through the US patient support program and agreed to participate in the study. Data were collected between January 2018 and January 2020 and the analysis was completed in May 2020. Clinically driven treatment with dupilumab. Disease control measured by the Atopic Dermatitis Control Tool (ADCT); concomitant AD therapies; satisfaction with therapy; skin symptoms (skin pain/soreness, hot/burning feeling, sensitivity to touch) assessed using numerical rating scales; flares; health-related quality of life assessed using the Dermatology Life Quality Index; sleep problems assessed using the ADCT item and a stand-alone question; and the AD-specific Work Productivity and Activity Impairment Questionnaire. Of 699 patients who initiated dupilumab (431 [61.7%] female, 515 [73.7%] White), 632 and 483 completed the survey at months 1 and 12, respectively. As-observed results showed that most patients achieved adequate disease control (ADCT total score) at month 1 with further improvement at month 12 (385 of 632 patients [60.9%] and 374 of 483 [77.4%] for the 2 time points, respectively, vs 41 of 699 [5.3%] at baseline; both P < .001). Use of other AD therapies was reduced at each follow-up vs baseline, including topical and systemic corticosteroids, which were reduced at month 12 to 40.4% (195 of 483 patients) and 6.2% (30 of 483 patients), respectively, from 68.1% (476 of 699) and 34.9% (244 of 699), respectively, at baseline (both P < .001 vs baseline). Patient satisfaction with AD treatment was higher than baseline (120 of 699 [17.7%]) at each follow-up to 85.1% (411 of 483) at month 12 (P < .001). At each follow-up, patients reported reductions in flares, itch, skin symptoms, and improved sleep, health-related quality of life, and daily activities vs baseline. Results were consistent based on observed data and imputed data using pattern mixture models for missing data. Consistent with patient-reported outcomes in clinical trials, this cohort study found that dupilumab treatment was associated with rapid and sustained disease control for up to 12 months as demonstrated by statistically significant improvements relative to baseline on all patient-reported outcomes including treatment satisfaction.

Abstract 2559: An analysis of patient-reported outcomes of radiation dermatitis in a multiracial/ethnic breast cancer population

Abstract More than half of cancer patients are treated with radiotherapy (RT), and many patients will develop acute radiation dermatitis (ARD) or skin reactions at some point during their treatment. In breast cancer, RT is a common adjuvant treatment and acute RT-induced dermatitis or skin reactions is a frequent side effect. Most acute RT-induced skin reactions resolve after several weeks, but some side effects persist and can cause serious complications. RD is reported by either the radiation oncologist or the patient and previous studies reported that there are disagreements between clinician-reported outcomes (CROs) and patient-reported outcomes (PROs). We have previously reported skin toxicity results using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). The current study focused on PROs of ARD symptoms that most frequently affect breast cancer patients and the degree that treatment impacted their normal daily activities. We evaluate the quality of life questionnaire administered on the last day of RT to 516 breast cancer patients receiving RT. Participants were asked to rate ARD-related symptoms on a 5-point Likert scale (0=Not bothered at all to 4=Very much). The symptoms measured were breast tenderness, pain, itching, warmth to touch, swelling, hyperpigmentation, blistering, thickening of the skin, hardness of breast, flaking, slow healing wounds, and erythema. Patients were also asked to rate the extent to which their treatment disrupted their normal daily activities on a 10-point Likert scale (0=Not all to 10=A lot). Hyperpigmentation was the most commonly reported symptom, with 25% of patients being highly bothered by the symptom. Erythema followed as the second most commonly reported symptom. Of the total 516 patients, 320 (77%) reported some form of disruption to their normal daily activities due to treatment. A number of the patient reported ARD-related symptoms differ by race/ethnicity, age, obesity, smoking history, and tumor stage. The results from a recent systematic review and meta-analysis, CROs and PROs of breast RD showed strong concordance. However, investigators concluded that clinicians reported significantly more acute edema, less acute breast pain, and less chronic breast shrinkage than patients. Considering the increasing combined application of CROs and PROs in clinical trials, our future research will highlight a critical issue regarding the accuracy of symptom reporting and subsequent management provided to patients. We will identify strategies to standardize items using a single tool to accurately and precisely estimate ARD from both the clinician and patient. Given the negative impact of ARD on patients' quality of life, further studies of ARD symptomology from both a patient and clinician standpoint are necessary to improve ARD management. Citation Format: Laura G. Acosta, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, George R. Yang, Jennifer J. Hu. An analysis of patient-reported outcomes of radiation dermatitis in a multiracial/ethnic breast cancer population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2559.