Assessing the Content Validity of Preference-Based Measures in Cancer.

OBJECTIVES: This study assessed the content validity of generic and condition-specific preference-based measures (PBMs) with patients treated for cancer, evaluated against 10 Consensus-Based Standards for the Selection of Health Measurement Instruments criteria for good content validity, to best inform measurement strategies regarding the use of PBMs in oncology development programs and real-world applications. METHODS: Individual, semistructured interviews were conducted with patients who received drug treatment for cancer in the United Kingdom (n = 47) and the United States (n = 49). During the interview, patients completed 3 generic PBMs (EQ-5D-5L, EuroQol Health and Wellbeing measure-Short Form, Château Santé Base) and 2 condition-specific PBMs (Quality of Life Utility-Core 10 Dimension, Functional Assessment of Cancer Therapy Eight Dimension [FACT-8D]). Interviews were conducted via teleconference, audio recorded, and transcribed verbatim. Transcripts were coded using thematic and content analysis methods. RESULTS: Condition-specific measures were evaluated as having better relevancy than generic PBMs. Overall, the FACT-8D was evaluated as holding the best content validity in terms of relevancy, and the EuroQol Health and Wellbeing measure-Short Form received the most favorable evaluation of relevancy for generic PBMs. All measures demonstrated comparable comprehensiveness, with all suggested by patients to be missing concepts. The EQ-5D-5L was evaluated best in terms of comprehensibility. This was followed by the Quality of Life Utility-Core 10 Dimension and FACT-8D; both received similar evaluations. CONCLUSIONS: All measures were generally seen by patients as adequate in capturing appropriate aspects of health-related quality of life for measuring cancer outcomes, although together condition-specific measures were evaluated as having better relevancy than generic PBMs. Further health-related quality of life instrument development is encouraged, particularly with regard to the longer-term detrimental impacts of cancer and treatment side effects. Other developments could include new cancer-specific tools inclusive of conventional health items, treatment impacts, and psychological items.

A Methodological Study to Compare Alternative Modes of Administration With Value EQ-5D Using Preference-Elicitation Techniques.

OBJECTIVES: Time trade-off (TTO) and discrete choice experiment (DCE) preference-elicitation techniques can be administered using face-to-face interviews (F2F), unassisted online (UO) surveys, or remote-assisted (RA) interviews. The objective of this study was to explore how the mode of administration affects the quality and reliability of preference-elicitation data. METHODS: EQ-5D-5L health states were valued using composite TTO (cTTO) and DCE approaches by the UK general population. Participants were allocated to 1 of 2 study groups. Group A completed both F2F and UO surveys (n = 271), and group B completed both RA and UO surveys (n = 223). The feasibility of survey completion and the reliability and face-validity of data collected were compared across all modes of administration. RESULTS: Fewer participants reported receiving sufficient guidance on the cTTO tasks during the UO survey compared with the 2 assisted modes. Participants across all modes typically reported receiving sufficient guidance on the DCE tasks. cTTO data were less reliable from the UO survey compared with both assisted modes, but there were no differences in DCE data reliability. cTTO data from all modes demonstrated face-validity; however, the UO survey produced higher utilities for moderate and severe health states than both assisted modes. Both F2F and RA modes provided comparably reliable data. CONCLUSIONS: The reliability of DCE data is not affected by the mode of administration. Interviewer-assisted modes of administration (F2F or RA) yield more reliable cTTO data than unassisted surveys. Both F2F and RA surveys produced similar-quality data.

A Review of Meaningful Change Thresholds for EORTC QLQ-C30 and FACT-G Within Oncology.

OBJECTIVES: This literature review provides an overview of meaningful change thresholds for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy - General (FACT-G) used across hematological cancers and solid tumors (melanoma, lung, bladder, and prostate). METHODS: Embase, MEDLINE, and PubMed were searched to identify relevant oncology publications from 2016 to 2021. Label claims from the US Food and Drug Administration and the European Medicines Agency for 7 recently approved drugs (pembrolizumab, atezolizumab, glasdegib, gilteritinib, tisagenlecleucel, axicabtagene ciloleucel, and daratumumab plus hyaluronidase-fihj) were reviewed. RESULTS: Publications providing guidance on meaningful change thresholds for the QLQ-C30 displayed a growing trend away from broad "legacy" thresholds of 10 points for all QLQ-C30 scales), toward deriving "contemporary" thresholds (eg, subscale specific, population specific). Contemporary publications generally provide guidance on selecting thresholds for specific scales that account for improved or worsening thresholds (eg, QLQ-C30 subscales). This trend was not clear for FACT-G, with less new guidance available. Most clinical trials used in regulatory label submissions have used thresholds of 10 points for the QLQ-C30 subscales and 3 to 7 points for the FACT-G total score. Despite the availability of more recent guidelines, contemporary meaningful change thresholds seem slow to emerge in the published literature and regulatory labels. CONCLUSIONS: Trialists should consider using contemporary thresholds, rather than legacy thresholds, for QLQ-C30 endpoints. Thresholds derived for a similar patient-population should be used where available. Further work is required to provide these across a broader range of cancer sites.

Administering selected subscales of patient-reported outcome questionnaires to reduce patient burden and increase relevance: a position statement on a modular approach.

Patient-reported outcome (PRO) questionnaires considered in this paper contain multiple subscales, although not all subscales are equally relevant for administration in all target patient populations. A group of measurement experts, developers, license holders, and other scientific-, regulatory-, payer-, and patient-focused stakeholders participated in a panel to discuss the benefits and challenges of a modular approach, defined here as administering a subset of subscales out of a multi-scaled PRO measure. This paper supports the position that it is acceptable, and sometimes preferable, to take a modular approach when administering PRO questionnaires, provided that certain conditions have been met and a rigorous selection process performed. Based on the experiences and perspectives of all stakeholders, using a modular approach can reduce patient burden and increase the relevancy of the items administered, and thereby improve measurement precision and eliminate wasted data without sacrificing the scientific validity and utility of the instrument. The panelists agreed that implementing a modular approach is not expected to have a meaningful impact on item responses, subscale scores, variability, reliability, validity, and effect size estimates; however, collecting additional evidence for the impact of context may be desirable. It is also important to recognize that adequate rationale and evidence (e.g., of fit-for-purpose status and relevance to patients) and a robust consensus process that includes patient perspectives are required to inform selection of subscales, as in any other measurement circumstance, is expected. We believe that the considerations discussed within (content validity, administration context, and psychometric factors) are relevant across multiple therapeutic areas.

International Society for Quality of Life Research commentary on the US Food and Drug Administration draft guidance for industry on core patient-reported outcomes in cancer clinical trials.

In June 2021, the US Food and Drug Administration (FDA) released a draft guidance for industry on core patient-reported outcomes (PROs) and related considerations for instrument selection and trial design in registrational cancer clinical trials, building on prior communications about the use of PROs to assess efficacy and tolerability in oncology drug development. The International Society for Quality of Life Research (ISOQOL) Standards and Best Practices Committee led an initiative to draft a commentary about the guidance, focusing on its positive aspects and areas that would benefit from additional clarification and consideration. For comprehensiveness, the authors reviewed existing public comments on the draft guidance, and the commentary underwent a thorough review process through three ISOQOL Special Interest Groups (Psychometrics, Clinical Practice, and Regulatory and Health Technology Assessment Engagement) followed by the ISOQOL Board. The goal of this commentary is to situate this new and relevant guidance document within the context of recent regulatory efforts on PROs and highlight areas in which further work may ultimately benefit the field.

Equivalence testing of a newly developed interviewer-led telephone script for the EORTC QLQ-C30.

PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core Questionnaire (QLQ-C30) is a widely used generic self-report measure of health-related quality of life (HRQOL) for cancer patients. However, no validated voice script for interviewer-led telephone administration was previously available. The aim of this study was to develop a voice script for interviewer administration via telephone. METHODS: Following guidelines from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) PRO Mixed Modes Good Research Practices Task Force, a randomised cross-over equivalence study, including cognitive debriefing, was conducted to assess equivalence between paper and telephone administration modes. Assuming an expected intraclass correlation coefficient (ICC) of 0.70 and a minimally acceptable level of 0.50, a sample size of 63 was required. RESULTS: Cognitive interviews with five cancer patients found the voice script to be clear and understandable. Due to a protocol deviation in the first wave of testing, only 26 patients were available for analyses. A second wave of recruitment was conducted, adding 37 patients (n = 63; mean age 55.48; 65.1% female). Total ICCs for mode comparison ranged from 0.72 (nausea and vomiting, 95% CI 0.48-0.86) to 0.90 (global health status/QoL, 95% CI 0.80-0.95; pain, 95% CI 0.79-0.95; constipation, 95% CI 0.80-0.95). For paper first administration, all ICCs were above 0.70, except nausea and vomiting (ICC 0.55; 95% CI 0.24-0.76) and financial difficulties (ICC 0.60; 95% CI 0.31-0.79). For phone first administration, all ICCs were above 0.70. CONCLUSIONS: The equivalence testing results support the voice script's validity for administration of the QLQ-C30 via telephone.

Mapping EQ-5D-3L to EQ-5D-5L.

OBJECTIVES: The original 3-level EQ-5D (EQ-5D-3L) includes 5 dimensions with 3 levels of problems per dimension. Since 2010, a more sensitive version with 5 levels of problems per dimension (EQ-5D-5L) has become available. Population value sets have been developed for both versions of the questionnaire. The objective of this research was to develop a mapping function to link EQ-5D-3L responses to value sets for the EQ-5D-5L. METHODS: Various algorithms were developed to link EQ-5D-3L and EQ-5D-5L responses using data from an observational study including members of 10 subgroups (N = 3580) who completed both versions of the questionnaire. Nonparametric and ordinal logistic regression models were fit to the data and compared using Akaike's information criterion (AIC) as well as the mean absolute error and root mean squared error of predictions. Results were contrasted qualitatively and quantitatively with those of an alternative copula-based approach. RESULTS: Including indicants of problems for other EQ-5D-3L dimensions as regressors in the modeling yielded the greatest improvement in prediction accuracy. Adding age and gender lowered the AIC without improving predictions, while including a latent factor lowered the AIC further and slightly improved predictive accuracy. Models that conditioned on problems in other EQ-5D-3L dimensions yielded more accurate predictions than the alternative copula-based approach in subgroups defined by age and gender. CONCLUSION: We present novel algorithms to map EQ-5D-3L responses to EQ-5D-5L value sets. The recommended approach is based on an ordinal logistic regression that disregards age and gender and accounts for unobserved heterogeneity using a latent factor.

A Comparison of Generic and Condition-Specific Preference-Based Measures Using Data From Nivolumab Trials: EQ-5D-3L, Mapping to the EQ-5D-5L, and European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions.

OBJECTIVES: There is growing interest in condition-specific preference measures, including the European Organisation for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (QLU-C10D). This research assessed the implications of using utility indices on the basis of the EQ-5D-3L, a mapping of EQ-5D-3L to the EQ-5D-5L, and the QLU-C10D, and compared their psychometric properties. METHODS: Data were taken from 8 phase 3 randomized controlled trials of nivolumab with or without ipilimumab for the treatment of solid tumors. Utilities for progression-related states were calculated using the UK and English value sets and incremental quality-adjusted life-years (QALYs) derived from established UK cost-effectiveness models. The psychometric properties of the utility indices were assessed using pooled trial data. RESULTS: Compared with the EQ-5D-3L index, the mapped EQ-5D-5L index yielded an average of 6% more and the QLU-C10D index an average of 2% fewer incremental QALYs for nivolumab versus comparators. All indices could differentiate between groups defined by performance status, cancer stage, or self-reported health status at baseline and detect meaningful changes in performance status, tumor response, health status, and quality of life over approximately 12 weeks of treatment. CONCLUSIONS: The lower QALY yield of the QLU-C10D was balanced by evidence of greater validity and responsiveness. Benefits gained from using the QLU-C10D may be apparent when treatments affect targeted symptoms and functional aspects, including sleep, bowel function, appetite, nausea, and fatigue. The observed differences in QALYs may not be sufficiently large to affect health technology assessment decisions.

Does recall period matter? Comparing PROMIS® physical function with no recall, 24-hr recall, and 7-day recall.

PURPOSE: To evaluate the influence of recall periods on the assessment of physical function, we compared, in cancer and general population samples, the standard administration of PROMIS Physical Function items without a recall period to administrations with 24-hour and 7-day recall periods. METHODS: We administered 31 items from the PROMIS Physical Function v2.0 item bank to 2400 respondents (n = 1001 with cancer; n = 1399 from the general population). Respondents were randomly assigned to one of three recall conditions (no recall, 24-hours, or 7-days) and one of two "reminder" conditions (with recall periods presented only at the start of the survey or with every item). We assessed items for potential differential item functioning (DIF) by recall time period. We then tested recall and reminder effects with analysis of variance controlling for demographics, English fluency, and co-morbidities. RESULTS: Based on conservative pre-set criteria, no items were flagged for recall time period-related DIF. Using analysis of variance, each condition was compared to the standard PROMIS administration for Physical Function (no recall period). There was no evidence of significant differences among groups in the cancer sample. In the general population sample, only the 24-hour recall condition with reminders was significantly different from the "no recall" PROMIS standard. At the item level, for both samples, the number of items with non-trivial effect size differences across conditions was minimal. CONCLUSIONS: Compared to no recall, the use of a recall period has little to no effect upon PROMIS physical function responses or scores. We recommend that PROMIS Physical Function be administered with the standard PROMIS "no recall" period.

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.

BACKGROUND: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. METHODS: In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. RESULTS: The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. CONCLUSIONS: Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

United States Valuation of EQ-5D-5L Health States Using an International Protocol.

OBJECTIVE: To derive a US-based value set for the EQ-5D-5L questionnaire using an international, standardized protocol developed by the EuroQol Group. METHODS: Respondents from the US adult population were quota-sampled on the basis of age, sex, ethnicity, and race. Trained interviewers guided participants in completing composite time trade-off (cTTO) and discrete choice experiment (DCE) tasks using the EuroQol Valuation Technology software and routine quality control measures. Data were modeled using a Tobit model for cTTO data, a mixed logit model for DCE data, and a hybrid model that combined cTTO and DCE data. Model performance was compared on the basis of logical ordering of coefficients, statistical significance, parsimony, and theoretical considerations. RESULTS: Of 1134 respondents, 1062, 1099, and 1102 respondents provided useable cTTO, DCE, and cTTO or DCE responses, respectively, on the basis of quality control criteria and interviewer judgment. Respondent demographic characteristics and health status were similar to the 2015 US Census. The Tobit model was selected as the preferred model to generate the value set. Values ranged from -0.573 (55 555) to 1 (11 111), with 20% of all predicted health states scores less than 0 (ie, worse than dead). CONCLUSIONS: A societal value set for the EQ-5D-5L was developed that can be used for economic evaluations and decision making in US health systems. The internationally established, standardized protocol used to develop this US-based value set was recommended by the EuroQol Group and can facilitate cross-country comparisons.

A comparison of self-rated health using EQ-5D VAS in the United States in 2002 and 2017.

PURPOSE: To compare self-rated health among the United States general population in 2002 and 2017. METHODS: Secondary data were analyzed from two EQ-5D valuation studies conducted in 2002 and 2017. Both studies included the EQ-5D-3L self-classifier and visual analog scale (VAS), where health is rated from 0 (worst imaginable health) to 100 (best imaginable health). VAS scores were compared between time points using regression models, adjusting for sociodemographic factors (Model 1), plus illness (Model 2), and health problems according to the EQ-5D classifier (Model 3). RESULTS: Mean VAS scores in 2002 [84.4 (SD = 16.1)] were not different from 2017 [84.6 (SD = 14.5)] (p = 0.63), nor different after adjusting for demographics (Model 1) or illness (Model 2). However, 2017 VAS mean scores were significantly higher than 2002 [2.2 (95% CI 1.36-3.10)] upon adjusting for the presence of dimension-specific health problems. CONCLUSIONS: Self-rated health of the general US adult population in 2017 was similar to 2002, but after adjusting for health problems, scores were slightly higher in 2017. Sociodemographic shifts in age and education explain some of the differences in scores, and by removing health and sociodemographic factors, we found the VAS reveals self-rated health is slightly better in 2017 than 2002.

Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial.

BACKGROUND: Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). METHODS: CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. FINDINGS: Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs -7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires. INTERPRETATION: In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. FUNDING: Bristol-Myers Squibb.

Impact of JIA on parents' work absences.

OBJECTIVE: Children with JIA have long-term morbidity and require extensive parental assistance. This study aimed to evaluate the impact of having a child with JIA on parents' missed work time, which can lead to decreased work productivity. METHODS: The Truven Health MarketScan Commercial Database (2000-9) was accessed to identify a cohort of parents having a child with newly diagnosed JIA. For comparison, a cohort of parents having no children with JIA was identified and matched with the preceding cohort. Parents' work absences were analysed using descriptive statistics and multivariable regression. Estimates were weighted to be generalizable to the US employer-sponsored insurance population. RESULTS: The study identified 108 parents having a child with newly diagnosed JIA (mean age 42.5 years), representing an estimated 3335 (weighted) parents nationally. Most of them were from the South (45%), male (71%) and employed in the transportation and utilities industry (58%). The demographic characteristics of the control cohort of parents were generally similar. Children with JIA (mean age 10.6 years) represented an estimated 3528 cases nationally. The mean number of reported missed work-time hours was 281.81 (s.e. 40.50) in a 9 year period for parents having a child with JIA compared with other parents 183.36 (28.55). Work-time loss was significantly related to having a child with JIA, sex and geographical region of residence. Parents having a child with JIA were 2.78 times more likely to report work-time loss [odds ratio (OR) 2.78 (95% CI 1.47, 5.26)] than those having no children with JIA. CONCLUSION: Parents having a child with JIA report significant work-time loss compared with parents with no children having JIA, particularly during the year following the child's diagnosis.

Modelling Health State Utilities as a Transformation of Time to Death in Patients with Non-Small Cell Lung Cancer.

BACKGROUND: When utilities are analyzed by time to death (TTD), this has historically been implemented by 'grouping' observations as discrete time periods to create health state utilities. We extended the approach to use continuous functions, avoiding assumptions around groupings. The resulting models were used to test the concept with data from different regions and different country tariffs. METHODS: Five-year follow-up in advanced non-small cell lung cancer (NSCLC) was used to fit six continuous TTD models using generalized estimating equations, which were compared with progression-based utilities and previously published TTD groupings. Sensitivity analyses were performed using only patients with a confirmed death, the last year of life only, and artificially censoring data at 24 months. The statistically best-fitting model was then applied to data subsets by region and different EQ-5D-3L country tariffs. RESULTS: Continuous (natural) [Formula: see text] and [Formula: see text] models outperformed other continuous models, grouped TTD, and progression-based models in statistical fit (mean absolute error and Quasi Information Criterion). This held through sensitivity and scenario analyses. The pattern of reduced utility as a patient approaches death was consistent across regions and EQ-5D tariffs using the preferred [Formula: see text] model. CONCLUSIONS: The use of continuous models provides a statistically better fit than TTD groupings, without the need for strong assumptions about the health states experienced by patients. Where a TTD approach is merited for use in modelling, continuous functions should be considered, with the scope for further improvements in statistical fit by both widening the number of candidate models tested and the therapeutic areas investigated.

A Review of the Use of EQ-5D for Clinical Outcome Assessment in Health Technology Assessment, Regulatory Claims, and Published Literature.

The aim is to identify the extent to which EQ-5D is used as a clinical outcome assessment (COA) endpoint in a non-economic context in health technology assessment (HTA) decisions, regulatory labelling claims and published literature. Drug technology appraisals (TAs) published by HTA agencies in England, France, Germany and the USA between 2019 and 2021 were identified. Product labelling for drugs approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) between 2016 and 2021 were also identified. A systematic literature review (SLR) was also performed. Documents reporting EQ-5D in the context of economic evaluation only were excluded. EQ-5D data were reported for COA in 195 of 1072 (18%) published TAs, with the majority reported for Germany (n = 138). The EQ-5D visual analogue scale (EQ-VAS) was reported most frequently, in 68% of all TAs, and accounted for 100% of Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) and 94% of Gemeinsamer Bundesausschuss (G-BA) TAs. In total, 320 drugs were approved or reviewed by the EMA and 735 by the FDA. Of these, 15 reported EQ-5D data from the EMA and 35 from the FDA; however, all EQ-5D data submitted to the FDA were reported in supporting documentation. Reporting of both EQ-5D index and EQ-VAS was most frequent, occurring in 32% of all documents. For the SLR, 329 of 4248 (8%) retrieved records were included. Reporting of both EQ-5D index and EQ-VAS was most frequent, occurring in 36% of studies. Clinical evaluation of recent drug approvals, based on regulatory, HTA and systematic literature reviews, demonstrated limited use of EQ-5D outside the context of economic evaluations. This may be due to the likelihood that the EQ-5D may lack sensitivity to detect improvement in conditions with small expected therapeutic benefit, or because the EQ-5D is not considered an adequate COA tool for clinical evaluation of treatment benefit. EQ-5D, as a COA, was more likely to be used in clinical evaluation of cancer drugs than drugs for treatment in any other disease category. HTA bodies were more likely to use the EQ-5D for COA, especially in Germany.

Comparison of Preferences and Data Quality between Discrete Choice Experiments Conducted in Online and Face-to-Face Respondents.

INTRODUCTION: Discrete choice experiments (DCE) are increasingly being conducted using online panels. However, the comparability of such DCE-based preferences to traditional modes of data collection (e.g., in-person) is not well established. In this study, supervised, face-to-face DCE was compared with its unsupervised, online facsimile on face validity, respondent behavior, and modeled preferences. METHODS: Data from face-to-face and online EQ-5D-5L health state valuation studies were compared, in which each used the same experimental design and quota sampling procedure. Respondents completed 7 binary DCE tasks comparing 2 EQ-5D-5L health states presented side by side (health states A and B). Data face validity was assessed by comparing preference patterns as a function of the severity difference between 2 health states within a task. The prevalence of potentially suspicious choice patterns (i.e., all As, all Bs, and alternating As/Bs) was compared between studies. Preference data were modeled using multinomial logit regression and compared based on dimensional contribution to overall scale and importance ranking of dimension-levels. RESULTS: One thousand five Online respondents and 1,099 face-to-face screened (F2FS) respondents were included in the main comparison of DCE tasks. Online respondents reported more problems on all EQ-5D dimensions except for Mobility. The face validity of the data was similar between comparators. Online respondents had a greater prevalence of potentially suspicious DCE choice patterns ([Online]: 5.3% [F2FS] 2.9%, P = 0.005). When modeled, the relative contribution of each EQ-5D dimension differed between modes of administration. Online respondents weighed Mobility more importantly and Anxiety/Depression less importantly. DISCUSSION: Although assessments of face validity were similar between Online and F2FS, modeled preferences differed. Future analyses are needed to clarify whether differences are attributable to preference or data quality variation between modes of data collection.

General population reference values for the Functional Assessment of Cancer Therapy-Lung and PROMIS-29.

BACKGROUND: Therapeutic advances in lung cancer have turned attention toward patient-reported outcome measures (PROMs) as important clinical outcomes. The Functional Assessment of Cancer Therapy-Lung (FACT-L) is a common endpoint in lung cancer trials. This study calculated FACT-L reference values for the United States (US) general population. METHODS: Adults from the US general population (N = 2001) were surveyed between September 2020 and November 2020. Surveys contained 126 questions, including the FACT-L [36 items; FACT-G and four subscales (Physical Well-Being [PWB], Social Well-Being [SWB], Emotional Well-Being [EWB], and Functional Well-Being [FWB]) and the Lung Cancer Subscale (LCS), and a Trial Outcome Index (TOI)]. Reference values for each FACT-L scale were calculated with means for the total sample and separately for participants with: no comorbidities, COVID-19 as only comorbidity, no COVID-19. RESULTS: In the total sample, the reference scores were as follows: PWB = 23.1; SWB = 16.8; EWB = 18.5; FWB = 17.6; FACT-G = 76.0; LCS = 23.0, TOI = 63.7, and FACT-L Total = 99.0. Scores were lower for those reporting a prior diagnosis of COVID-19, especially for SWB (15.7) and FWB (15.3). SWB scores were lower than previous references values. CONCLUSIONS: These data provide US general adult population reference value set for FACT-L. While some of the subscale results were lower than those found in the reference data for other PROMs, these data were obtained in a more contemporaneous time frame juxtaposed with the COVID-19 pandemic and may represent a new peri-pandemic norm. Thus, these reference values will be useful for future clinical research.

Effects of aromatase inhibition versus gonadectomy on hippocampal complex amyloid pathology in triple transgenic mice.

Alzheimer's disease (AD) is the most common form of dementia among the elderly with women exhibiting a higher risk than men for the disease. Due to these gender differences, there is great interest in the role that estrogens play in cognitive impairment and the onset of the classic amyloid and tau lesions in AD. Human and rodent studies indicate a strong association between low brain aromatase, sex hormone levels, and beta amyloid deposition. Therefore, the effects of depleting both circulating and brain estrogen levels, through gonadectomy and/or treatment with the aromatase inhibitor, anastrozole, upon hippocampal AD-like pathology in male and female 3xTgAD mice were evaluated. Liquid chromatography-mass spectrometry revealed anastrozole serum levels of 10.19 ng/mL and for the first time brain levels were detected at 4.7 pg/mL. Densitometric analysis of the hippocampus revealed that anastrozole significantly increased Aß- but not APP/Aß-immunoreactivity in intact 3xTgAD females compared to controls (p<0.001). Moreover, anastrozole significantly increased the number of Aß- compared to APP/Aß-positive hippocampal CA1 neurons in intact and gonadectomized female mice. Concurrently, anastrozole significantly reduced the APP/Aß plaque load in 9 month old female 3xTgAD mice. These data suggest that anastrozole treatment differentially affects select amyloid species which in turn may play a role in the extraneuronal to intraneuronal deposition of this peptide.

Comparison of two health-promotion programs for older workers.

OBJECTIVES: We examined the effects of 2 worksite health-promotion interventions (compared with a health-education control) on older workers' healthy behaviors and health outcomes. METHODS: We conducted a prospective, randomized controlled trial with 423 participants aged 40 years and older. Participants were categorized into 3 study arms: the COACH intervention combined Web-based risk assessments with personal coaching support, the RealAge intervention used a Web-based risk assessment and behavior-specific modules, and a control group received printed health-promotion materials. Participants were assessed at baseline, 6 months, and 12 months. Random-effects modeling controlled for baseline stage of change for all behaviors of interest in all groups. RESULTS: At 6 and 12 months, COACH participants showed significantly increased fruit and vegetable consumption (P = .026; P < .001) and participation in physical activity (P = .05; P = .013), and at 12 months they showed decreased percentage of energy from fat (P = .027). RealAge participants showed significantly decreased waist circumference at 6 and 12 months (P = .05; P = .018). CONCLUSIONS: COACH participants were twice as likely to use the COACH intervention as RealAge participants were to use the RealAge intervention. COACH participants experienced twice the number of positive outcomes that control participants experienced.