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Jennifer Dine,1 Yanfen Guan,2 Mirline Milien,1 Claire Ervin,1 Dana D Byrne,2 Michelle L Brown,2 Carisa De Anda,2 Josephine M Norquist2 1RTI Health Solutions, Research Triangle Park, Durham, NC, USA; 2Merck & Co., Inc., Rahway, NJ, USACorrespondence: Jennifer Dine, Patient-Centered Outcomes Assessment, RTI Health Solutions, 3040 E Cornwallis Road, Research Triangle Park, Durham, NC, 27709, USA, Email jdine@rti.orgIntroduction: The COVID-19 Symptoms Daily Diary (CSDD) is a patient-reported outcome measure designed to assess the severity of core COVID-19 symptoms in clinical trials. The preliminary version of the CSDD was developed based on regulatory guidance and the hallmark COVID-19 symptoms identified by the CDC. This study aimed to evaluate CSDD content validity, to determine whether it is fit for the purpose of supporting efficacy endpoints in clinical trials of treatments for COVID-19. This research also sought to evaluate the appropriateness of a newly developed Pre–COVID-19 Symptoms Questionnaire.Methods: A targeted literature review was completed to evaluate the relevance of concepts included in the diary and to identify any important symptoms that may have been missing. Hybrid (concept elicitation and cognitive debriefing) semistructured qualitative interviews were then conducted across 3 iterative rounds with 30 adults in the United States recently diagnosed with COVID-19.Results: The CSDD included concepts that were most frequently reported by interview participants, including those identified as most bothersome and most important to treat. During cognitive debriefing, participants described the diary concepts as salient and reported the instructions, recall period, and response options as clear and appropriate. Only 2 of 15 CSDD items were modified across 3 interview rounds; specifically, definitions for the vomiting and diarrhea frequency items were clarified for consistent interpretation and response. Interview participants also reported general ease in understanding and responding to the Pre–COVID-19 questionnaire, with feedback resulting in only minor changes to the reference period and instructions.Conclusion: The findings of the current study provide strong evidence for the content validity of the CSDD and the appropriateness of each of the items assessed. This rigorous evaluation (aligned with regulatory guidance) indicates that the CSDD is fit for the purpose of supporting efficacy endpoints in planned clinical trials evaluating medications for COVID-19 treatment.Keywords: patient-reported outcome measures, COVID-19, qualitative, symptom burden

Abstract Background The literature on changes in health-related quality of life (HRQOL) in weight loss studies is inconsistent, and few studies use more than one type of measure. The purpose of the current study was to compare one-year changes in HRQOL as a function of weight change using three different measures: a weight-related measure (Impact of Weight on Quality of Life-Lite [IWQOL-Lite)]) and two generic measures (SF-36; EQ-5D). Methods Data were obtained from 926 participants (mean Body Mass Index (BMI) (kg/m2) = 35.4; 84% female; mean age = 49.5 years) in a placebo-controlled randomized trial for weight loss. At baseline and one-year, participants completed all three HRQOL measures. HRQOL was compared across weight change categories (≥ 5% and 0–4.9% gain, 0–4.9%, 5.0–9.9% and ≥ 10% loss), using effect sizes. Results The weight-related measure of HRQOL exhibited greater improvements with one-year weight loss than either of the generic instruments, with effect sizes ranging from 0.24 to 0.62 for 5–9.9% weight reductions and 0.44 to 0.95 for ≥ 10% reductions. IWQOL-Lite Self-Esteem also showed a small improvement with weight gain. Changes in the two generic measures of HRQOL were inconsistent with each other, and in the case of the SF-36, variable across domains. For participants gaining ≥ 5% of weight, the greatest reductions in HRQOL occurred with respect to SF-36 Mental Health, MCS, and Vitality, with effect sizes of -0.82, -0.70, and -0.63 respectively. Conclusion This study found differences between weight-related and generic measures of health-related quality of life in a one-year weight loss trial, reflecting the potential value of using more than one measure in a trial. Although weight loss was generally associated with improved IWQOL-Lite, physical SF-36 subscale and EQ-5D scores, a small amount of weight gain was associated with a slight improvement on weight-specific HRQOL and almost no change on the EQ-5D, suggesting the need for further research to more fully study these relationships. We believe our findings have relevance for weight loss patients and obesity clinicians/researchers in informing them of likely HRQOL outcomes associated with varying amounts of weight loss or gain.

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in older adults. Despite a number of RSV vaccine candidates in clinical trials, there are no existing disease-specific, self-reported measures that assess the symptoms and severity of RSV infection from the perspective of adult patients with acute RSV. The objective of this study was to describe the initial conceptualization and development of the RSV Infection, Intensity and Impact Questionnaire (RSV-iiiQ), a new patient-reported outcome measure., Methods: A targeted review of the literature identified relevant existing measures, symptoms, and impacts of RSV. A draft version of the RSV-iiiQ was developed based on the Influenza Intensity and Impact Questionnaire (Flu-iiQ) with expert input. Qualitative interviews (N = 20) were conducted with participants to optimize the RSV-iiiQ conceptual model and confirm the content validity of the RSV-iiiQ. Interviews included concept elicitation and a cognitive debriefing assessment. A draft conceptual framework was developed, and the electronic clinical outcome assessment was piloted. All steps of instrument development followed Food and Drug Administration guidance for patient-reported outcomes., Results: In-depth concept elicitation interviews followed by cognitive debriefings demonstrated that the content of the items was comprehensive, covered the breadth of RSV symptoms and impacts, and was relevant to the experiences of individuals with RSV. Both the paper and electronic versions of the RSV-iiiQ were easily completed. Minor refinements were made to some items based on participant feedback, and the draft conceptual framework was refined., Conclusions: The RSV-iiiQ was developed for use in clinical trials to measure the symptom intensity and impact of acute RSV infection from the perspective of adult patients. The tool was developed in accordance with current regulatory guidance and is useful to support patient-focused drug development., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Background: In the randomised phase III KEYNOTE-062 study, pembrolizumab was non-inferior to chemotherapy for overall survival in patients with programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (GEJ) cancer. We present findings of prespecified health-related quality-of-life (HRQOL) analyses for pembrolizumab versus chemotherapy in this population., Materials and Methods: HRQOL, a secondary endpoint, was measured in patients who received ≥1 dose of study treatment and completed ≥1 HRQOL questionnaire [European Organisation for the Research and Treatment of Cancer (EORTC) 30-question quality-of-life (QLQ-C30), EORTC 22-question quality-of-life gastric-cancer-specific module (QLQ-STO22)]. Least squares mean (LSM) change (baseline to week 18) in global health status/quality of life (GHS/QOL; EORTC QLQ-C30) and time to deterioration (TTD) in GHS/QOL, nausea/vomiting and appetite loss scores (EORTC QLQ-C30) and abdominal pain/discomfort scores (EORTC QLQ-STO22) were evaluated., Results: The HRQOL population comprised 495 patients with CPS ≥1 (pembrolizumab, 252; chemotherapy, 243). Compliance rates at week 18 were similar for pembrolizumab and chemotherapy (EORTC QLQ-C30, 87.9% and 81.9%; EORTC QLQ-STO22, 87.9% and 81.3%, respectively). There was no between-arm difference in LSM score change in GHS/QOL [-0.16; 95% confidence interval (CI) -5.01 to 4.69; P = 0.948]. The LSM score change for most subscales showed comparable worsening in both arms. TTD for GHS/QOL [hazard ratio (HR), 0.96; 95% CI, 0.67-1.38; P = 0.826], appetite loss (HR, 0.83; 95% CI, 0.58-1.20; P = 0.314) and pain (HR, 1.22; 95% CI, 0.78-1.91; P = 0.381) were similar between arms. Longer TTD was observed for pembrolizumab versus chemotherapy for nausea/vomiting (HR, 0.61; 95% CI, 0.44-0.85; P = 0.003)., Conclusions: HRQOL was maintained with first-line treatment with pembrolizumab in patients with PD-L1-positive advanced gastric/GEJ cancer and was similar between pembrolizumab and chemotherapy in this population., Competing Interests: Disclosure EVC reports advisory/consultancy fees from Array, AstraZeneca, Bayer, BioPharma, Bristol Myers Squibb, Celgene, Halozyme, Lilly, Merck KGaA, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Roche and Servier; and researching grant/funding (institution) from Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA., Merck KGaA, Novartis, Roche and Servier. AV is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Y-JB reports consulting/advisory role for Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daichii-Sankyo, Eli Lilly, Genentech/Roche, Genexine, Green Cross, Hanmi, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Novartis, Samyang Biopharmaceuticals and Taiho; and grants (to the institution for clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Boston Biomedical, CKD Pharma, Curis, Daiichi Sankyo, Eli Lilly, Five Prime, Genentech/Roche, Genexine, Green Cross, GSK, MacroGenics, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Novartis, Ono, Pfizer, Taiho and Takeda. CSF reports consulting role for Agios, Amylin Pharmaceuticals, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Taiho and Unum Therapeutics. He also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health. He is a co-founder of EvolveImmune Therapeutics and has equity in this private company. KS reports grants and personal fees from Astellas Pharma, Eli Lilly and Company, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Ono Pharmaceutical and Taiho Pharmaceutical; personal fees from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Pfizer Inc., Takeda Pharmaceuticals and Yakult; and grants from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma and Medi Science. YYJ reports advisory fees from Bristol Myers Squibb, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono and Pfizer; and research expenses from Amgen, Bayer, Boehringer Ingelheim, Genentech, Lilly and Roche. VS reports research funding from Bristol Myers Squibb, EMD-Serono and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. SSt reports advisory/consultancy role for Bayer, Bristol Myers Squibb, Exelixis, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and QED. JMN is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. UK is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. SSh is an employee and a stockholder of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MA reports scientific consultancy role for Bristol Myers Squibb, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Servier; and honoraria for speaking for Bristol Myers Squibb, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Servier. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Patient-reported outcomes (PROs) are used in clinical trials to provide valuable evidence on the impact of disease and treatment on patients' symptoms, function and quality of life. High-quality PRO data from trials can inform shared decision-making, regulatory and economic analyses and health policy. Recent evidence suggests the PRO content of past trial protocols was often incomplete or unclear, leading to research waste. To address this issue, international, consensus-based, PRO-specific guidelines were developed: the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-PRO Extension. The SPIRIT-PRO Extension is a 16-item checklist which aims to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection to minimise research waste, and ultimately better inform patient-centred care. This SPIRIT-PRO explanation and elaboration (E&E) paper provides information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template. For each SPIRIT-PRO item, we provide a detailed description, one or more examples from existing trial protocols and supporting empirical evidence of the item's importance. We recommend this paper and protocol template be used alongside the SPIRIT 2013 and SPIRIT-PRO Extension paper to optimise the transparent development and review of trial protocols with PROs., Competing Interests: Competing interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and declare: SPIRIT-PRO group members were reimbursed for travel/subsistence at the consensus meeting. MC is Director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, Director of the Centre for the Centre for Patient Reported Outcomes Research and is a National Institute for Health Research (NIHR) Senior Investigator. MC has received personal fees from Astellas, Takeda, Merck, Daiichi Sankyo, Glaukos, GSK and the Patient-Centred Outcomes Research Institute (PCORI) outside the submitted work. RM-B reports non-financial support from University of Birmingham. OA, DK and ARet report grants from NIHR. OA and DK report grants from Birmingham Biomedical Research Centre (BRC). OA reports grants from UCB Pharma and also receives funding from the Health Foundation and declares personal fees from Gilead Sciences Ltd. DK and ARet report grants from Innovate UK and Macmillan Cancer Support. DK reports grants from Kidney Research UK, NIHR SRMRC at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, personal fees from Merck, GSK. EB declares personal fees from Navigating Cancer, Sivan Healthcare, CareVive Systems and AstraZeneca. Bell reports other from AstraZeneca, is an employee with stock ownership and/or stock options in the company. JCC reports other from Pfizer Inc., and is an employee and a stockholder of Pfizer Inc. IG is a fully paid employee of Boehringer Ingelheim International GmbH. CE is Chair of the Government of Canada Interagency Advisory Panel on Research Ethics. LM reports non-financial support from Daiichi-Sankyo and Cell & Gene Therapy Catapult. Morel reports other from UCB. LN reports other from GlaxoSmithKline, including employment and ownership of stock in GSK. RS reports personal fees from BioMed Central and Pfizer, other from NHS England, NHSx, NDC, NCRI, NIHR, MRC CTU, GeL, Glasgow CTU, UCLH, LSHTM, Cancer Research UK, Macmillan, Warwick University, Warwick CTU and University of Birmingham. AW reports grants from NIHR and Innovate UK. All other authors have completed the ICMJE uniform disclosure form and declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The sublingual immunotherapy (SLIT) Report Card was developed to capture patient-reported local reactions from the administration of SLIT, based on the World Allergy Organization side-effect grading system. The objective was to evaluate understandability, usability, and translatability of the paper and electronic versions of the SLIT Report Card., Methods: Adults (aged 18+ years), adolescents (aged 12-17 years), and parents/caregivers and their children (aged 5-11 years) participated in two rounds of interviews, testing the paper version in Round 1, and both the paper and electronic versions in Round 2. Interviews assessed comprehension and usability by subjects. Translatability identified potential issues related to translation or cultural relevance., Results: Ten adults, ten adolescents, and ten parent/child dyads were interviewed. In general, subjects demonstrated a clear understanding of the instrument's content. However, some subjects were uncertain of or suggested clarifying the meaning of certain terms, including tablet, ulcer, taste alteration, uvula, nausea, and itching in the ear. The translatability assessment also identified uvula and nausea as potentially problematic for translation. Subjects could use the electronic device and found navigation 'easy', with only a few minor suggestions made to improve usability. Some wording and formatting changes were made based on subjects' feedback and the translatability assessment., Conclusion: The SLIT Report Card was refined following best practices for instrument development, including cognitive interviewing, usability, and translatability assessment. The refined SLIT Report Card is appropriate for comprehensively and systematically collecting SLIT-related local reactions directly from subjects in a clinical trial setting, taking into account the World Allergy Organization grading system.

Background: Patient-reported outcome (PRO) instruments are important tools for monitoring disease activity and response to treatment in clinical trials and clinical practice. In recent years, there have been movements away from traditional pen-and-paper PROs towards electronic administration. When using electronic PROs (ePROs), evidence that respondents complete ePROs in a similar way to their paper counterparts provides assurance that the two modes of administration are comparable or equivalent. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 item (EORTC QLQ-C30) and associated disease-specific modules are among the most widely used PROs in oncology. Although studies have evaluated the comparability and equivalence of electronic and original paper versions of the EORTC QLQ-C30, no such studies have been conducted to date for the head and neck cancer specific module (EORTC QLQ-H&N35)., Objective: This study aimed to qualitatively assess the comparability of paper and electronic versions of the EORTC QLQ-H&N35., Methods: Ten head and neck cancer patients in the United States underwent structured cognitive debriefing and usability interviews. An open randomized crossover design was used in which participants completed the two modes of administration allocated in a randomized order. Using a "think-aloud" process, participants were asked to speak their thoughts aloud while completing the EORTC QLQ-H&N35. They were thoroughly debriefed on their responses to determine consistency in interpretation and cognitive process when completing the instrument in both paper and electronic format., Results: Participants reported that the EORTC QLQ-H&N35 demonstrated excellent qualitative comparability between modes of administration. The proportion of noncomparable responses (ie, where the thought process used by participants for selecting responses appeared to be different) observed in the study was low (11/350 response pairs [35 items x 10 participants]; 3.1%). Evidence of noncomparability was observed for 9 of the 35 items of the EORTC QLQ-H&N35 and in no more than 2 participants per item. In addition, there were no apparent differences in level of comparability between individual participants or between modes of administration., Conclusions: Mode of administration does not affect participants' response to, or interpretation of, items in the EORTC QLQ-H&N35. The findings from this study add to the existing evidence supporting the use of electronic versions of the EORTC instruments when migrated to electronic platforms according to best practice guidelines., (©Josephine Norquist, Diana Chirovsky, Teja Munshi, Chloe Tolley, Charlotte Panter, Adam Gater. Originally published in JMIR Cancer (http://cancer.jmir.org), 12.05.2017.)

Purpose: Condition-specific measures may not always have independent items, yet existing techniques of developing health state utility values from these measures are inappropriate when items are not independent. This study develops methods for deriving and valuing health states for a condition-specific preference-based measure where items are not independent., Methods: The analysis has three stages: firstly, Rasch analysis is used to develop a health state classification system from the Flushing Symptoms Questionnaire (FSQ) that is amenable to valuation and to identify a set of health states for valuation. Secondly, a valuation survey of the health states using time-trade-off (TTO) methods is conducted to elicit health state values. Finally, regression models are applied to map the relationship between mean TTO values and Rasch logit values. The model is then used to estimate health state values for all possible health states., Results: Rasch models were fitted to 1,270 responders to the FSQ and a series of 16 health states were identified for the valuation exercise. An ordinary least squares model best described the relationship between mean TTO values and Rasch logit values (R (2) = 0.958; root mean square error = 0.042)., Conclusions: This study demonstrates how health state utility values can be mapped onto Rasch logit values in order to value all states defined by the FSQ, a condition-specific measure where items are not independent. This should significantly enhance research in this field.

In Middle-Eastern countries, more particularly in Lebanon, the incidence of vitamin D deficiency has been found to be surprisingly high in schoolchildren and young individuals. However, the prevalence and risk factors for vitamin D inadequacy amongst Lebanese osteoporotic women seeking medical health care has never been studied. We analysed vitamin D-inadequacy risk factors among the 251 Lebanese postmenopausal osteoporotic women (from both Muslim and Christian communities) who participated in a vitamin D international epidemiological study. Vitamin D inadequacy prevalence (25-hydroxyvitamin D (25(OH)D) , 30 ng/ml) was 84.9%. 25(OH)D was negatively correlated with BMI (r 20.41; P<0.001) and positively correlated with educational level (r 0.37; P<0.001) and self-reported general health (r 0.17; P<0.01). No significant correlation was found with age and no seasonal variation was observed. There was no significant correlation between 25(OH)D and sun exposure index or vitamin D-rich food consumption. However, 25(OH)D strongly correlated with vitamin D supplement intake (r 0.48; P<0.0001). Muslim community participants had lower 25(OH)D levels compared with their Christian counterparts (P<0.001). They also had higher BMI, lower educational level and vitamin D supplement consumption and followed more frequently a dress code covering the arms (P<0.0001 for all variables). In a multivariate model, in Muslims, inadequate vitamin D supplements and a dress code covering the arms are the independent predictors of 25(OH)D inadequacy (P<0.001 for both variables). However, in Christians, the predictors are inadequate vitamin D supplements, high BMI and low educational level (P<0.001; P=002 and P=0.02 respectively). There is an urgent need to increase vitamin D supplement use in Middle-Eastern osteoporotic women, more particularly in those from the Muslim community.