Marieke Krol

Background: The importance of clinical outcome assessments (COA) in healthcare decision making is increasingly recognised. However, evidence on associations between non-mandatory COA inclusion, health technology assessment (HTA) decision making, pricing, and sales of medicinal products is scarce. This study aimed to generate new insights into these associations. Methodology: HTA reports published in 2012–2022 by bodies in Germany (G-BA), France (HAS), and England (NICE) were retrieved and combined with pricing and sales data. Multiclassification machine learning models were built to analyse the associations between non-mandatory COA inclusion and HTA-related decision making and sales against other relevant features. For Germany, the association with pricing was analysed in addition. Results: Of 1506 identified HTA reports, 40.5% included non-mandatory COAs. In Germany and France, beneficial ratings were observed more often among HTA reports with non-mandatory COA (Germany: 47%, France: 42%) than among HTA reports without such COAs (12% and 24%, respectively). Non-mandatory COA inclusion was unrelated to HTA ratings in England. In Germany, rebates and achieved list price premiums did not differ significantly between HTA reports with and without non-mandatory COAs. Non-mandatory COA inclusion appeared among the model features in Germany and England, but not France. Given the low accuracy of the sales models, the sales findings should be regarded as exploratory only. Conclusions: In France and Germany, positive HTA ratings were more likely for medicinal products with HTA reports that included non-mandatory COAs. In Germany, achieved list price premiums were numerically higher for products with HTA reports that included non-mandatory COAs, although the difference was not statistically significant. In Germany and England, pricing and/or sales were numerically, but statistically insignificantly, higher. Sales models linked COA-related features to higher predicted sales categories in Germany and England. Exploratory sales models linked COA-related features to higher predicted sales categories in Germany and England. Given the low accuracy of the sales models, findings related to sales should be regarded as exploratory.

Background: Dyspnea is a prominent symptom in patients with warm autoimmune hemolytic anemia (wAIHA), yet its lived experience remain under-researched. Although clinically relevant, dyspnea is not routinely assessed in wAIHA trials, and no validated patient-reported outcome (PRO) measures exist for this population. This study explored patients’ experience of wAIHA-related dyspnea, identified its most bothersome impacts on daily life, and evaluated the content validity of the FACIT-Dyspnea 10-item Short Form (SF) in wAIHA. Methodology: Hybrid concept elicitation and cognitive debriefing interviews were conducted with 15 adults diagnosed with wAIHA in the US. Patients were recruited via recruitment vendors and a patient advocacy group. Interviews were conducted online, transcribed verbatim, and analyzed using inductive and deductive coding. Results: All fifteen patients (aged 35–74; 80% female) reported experiencing dyspnea, primarily triggered by physical exertion and alleviated by rest. Twelve (80%) patients reported dyspnea and fatigue exacerbated each other. Most were in remission with three receiving treatment at interview. Thirty-three distinct dyspnea-related impacts were identified, predominantly affecting physical functioning (e.g., difficulty walking) and activities of daily living (ADLs). Emotional (e.g., anxiety) and occupational impacts were also reported. These findings highlight dyspnea’s substantial effect on health-related quality of life (HRQoL).

Background: Many immunocompromised individuals continue to practice physical distancing behaviors to avoid severe COVID-19 outcomes. To measure the intensity of these physical distancing behaviors, we aimed to develop and validate a standardized metric across age groups: the Physical Distancing Scale for COVID-19 Avoidance (PDS-C19©). Methodology: PDS-C19 development involved content scoping, initial draft PDS-C19 design phase, and exploratory testing (via asynchronous online forums). Psychometric properties (structural validity, reliability, and construct validity) of the PDS-C19 were evaluated using a random sample of immunocompromised and non-immunocompromised participants ( n = 1059) of the EAGLE Study, including adults and children aged 0.5–17 years from the US and UK. Adult caregivers of children aged ≤ 12 years completed a proxy version of the PDS-C19 on their behalf, in addition to providing self-reported responses. Results: Findings from the two asynchronous forums ( n = 23 and n = 22) indicated that the items identified in the scoping phase were relevant and well-understood. As part of the structural validity analysis, item-response distributions, inter-item correlations, and exploratory factor analyses supported a nine-item unidimensional intensity scale. Confirmatory factor analyses reduced the PDS-C19 to seven items (two items were dropped due to high residual correlations or differential item functioning by age). Internal consistency was high (ω = 0.97); convergent validity was good, with high correlations ( r _max =0.74) with clinical outcome assessments of the ability to participate in activities and with worry. The PDS-C19 had good known-groups validity, with scores distinguishable by types of activities, level of worry, and number of close contacts. Conclusion: The PDS-C19 had acceptable structural and construct validity and high internal consistency, demonstrating its value as a measure of physical distancing to avoid COVID-19 in immunocompromised and non-immunocompromised individuals.

Background: Warm Autoimmune Hemolytic Anemia (wAIHA) is a rare form of anemia caused by premature destruction of red cells. This qualitative study aimed to understand the patient experience with wAIHA and provide evidence of FACIT-Fatigue scale validity by interviewing adult wAIHA patients along with examining patients’ definitions of meaningful change for item 1 of the FACIT Fatigue. Methods: Hybrid Concept Elicitation (CE) and Cognitive Debriefing (CD) interviews, lasting approximately 75 min, were conducted with US-based adults diagnosed with wAIHA. The CE part of the interview focused on understanding the patient's experiences with wAIHA, particularly the signs/symptoms, and impacts. The CD part evaluated patient’s feedback on clarity, relevance, and comprehensibility of the FACIT-Fatigue, and examined their interpretation of meaningful change for item 1. Results: Nineteen adult wAIHA patients (mean age 49.7 years) from the US were interviewed, 31 signs/symptoms were identified with fatigue being the most common (reported by all patients, 100%) and bothersome. In addition, many patients experienced shortness of breath (95%) and skin/eye color change (74%). Other common symptoms included headaches (63%), dark/brown urine (63%), heart palpitations (63%), and dizziness (53%). The study also found that wAIHA can have negative impact on patients’ emotional functioning, physical functioning, daily activities, social and professional life. The most frequently reported impacts included feeling anxious or scared (79%), difficulty climbing stairs (74%), needing help from others (74%), and reduced physical strength/mobility (74%). Patients also frequently reported feelings of anger/frustration (68%), needing frequent rests (68%), difficulty walking (68%), feeling worrisome (53%), and impacts on social activities (53%). A novel conceptual disease model was developed, highlighting the associations between symptoms and their impacts on patients’ lives. Patients indicated the FACIT-Fatigue was clear, relevant, and appropriate for measuring their wAIHA related fatigue. A 1-point score change in the item 1 was considered meaningful for both improvement and worsening of their fatigue by most patients. Conclusions: The study offers insight into the patient experience with wAIHA, detailing common symptoms and impacts on daily life as part of wAIHA conceptual disease model. It also supports the content validity of the FACIT-Fatigue instrument for assessing fatigue in wAIHA patients.

Background: Immunocompromised individuals are known to respond inadequately to SARS-CoV-2 vaccines, placing them at high risk of severe or fatal COVID-19. Thus, immunocompromised individuals and their caregivers may still practice varying degrees of social or physical distancing to avoid COVID-19. However, the association between physical distancing to avoid COVID-19 and quality of life has not been comprehensively evaluated in any study. Objective: We aim to measure physical distancing behaviors among immunocompromised individuals and the association between those behaviors and person-centric outcomes, including health-related quality of life (HRQoL) measures, health state utilities, anxiety and depression, and work and school productivity impairment. Methods: A patient-informed protocol was developed to conduct the EAGLE Study, a large cross-sectional, observational study, and this paper describes that protocol. EAGLE is designed to measure distancing behaviors and outcomes in immunocompromised individuals, including children (aged ≥6 mo) and their caregivers, and nonimmunocompromised adults in the United States and United Kingdom who report no receipt of passive immunization against COVID-19. We previously developed a novel self- and observer-reported instrument, the Physical Distancing Scale for COVID-19 Avoidance (PDS-C19), to measure physical distancing behavior levels cross-sectionally and retrospectively. Using an interim or a randomly selected subset of the study population, the PDS-C19 psychometric properties will be assessed, including structural validity, internal consistency, known-group validity, and convergent validity. Associations (correlations) will be assessed between the PDS-C19 and validated HRQoL-related measures and utilities. Structural equation modeling and regression will be used to assess these associations, adjusting for potential confounders. Participant recruitment and data collection took place from December 2022 to June 2023 using direct-to-patient channels, including panels, clinician referral, patient advocacy groups, and social media, with immunocompromising diagnosis confirmation collected and assessed for a randomly selected 25% of immunocompromised participants. The planned total sample size is 3718 participants and participant-caregiver pairs. Results will be reported by immunocompromised status, immunocompromising condition category, country, age group, and other subgroups. Results: All data analyses and reporting were planned to be completed by December 2023. Results are planned to be submitted for publication in peer-reviewed journals in 2024-2025. Conclusions: This study will quantify immunocompromised individuals’ physical distancing behaviors to avoid COVID-19 and their association with HRQoL as well as health state utilities. International Registered Report Identifier (IRRID): RR1-10.2196/52643

BACKGROUND Immunocompromised individuals are known to respond inadequately to SARS-CoV-2 vaccines, placing them at high risk of severe or fatal COVID-19. Thus, immunocompromised individuals and their caregivers may still practice varying degrees of social or physical distancing to avoid COVID-19. However, the association between physical distancing to avoid COVID-19 and quality of life has not been comprehensively evaluated in any study. OBJECTIVE We aim to measure physical distancing behaviors among immunocompromised individuals and the association between those behaviors and person-centric outcomes, including health-related quality of life (HRQoL) measures, health state utilities, anxiety and depression, and work and school productivity impairment. METHODS A patient-informed protocol was developed to conduct the EAGLE Study, a large cross-sectional, observational study, and this paper describes that protocol. EAGLE is designed to measure distancing behaviors and outcomes in immunocompromised individuals, including children (aged ≥6 mo) and their caregivers, and nonimmunocompromised adults in the United States and United Kingdom who report no receipt of passive immunization against COVID-19. We previously developed a novel self- and observer-reported instrument, the Physical Distancing Scale for COVID-19 Avoidance (PDS-C19), to measure physical distancing behavior levels cross-sectionally and retrospectively. Using an interim or a randomly selected subset of the study population, the PDS-C19 psychometric properties will be assessed, including structural validity, internal consistency, known-group validity, and convergent validity. Associations (correlations) will be assessed between the PDS-C19 and validated HRQoL-related measures and utilities. Structural equation modeling and regression will be used to assess these associations, adjusting for potential confounders. Participant recruitment and data collection took place from December 2022 to June 2023 using direct-to-patient channels, including panels, clinician referral, patient advocacy groups, and social media, with immunocompromising diagnosis confirmation collected and assessed for a randomly selected 25% of immunocompromised participants. The planned total sample size is 3718 participants and participant-caregiver pairs. Results will be reported by immunocompromised status, immunocompromising condition category, country, age group, and other subgroups. RESULTS All data analyses and reporting were planned to be completed by December 2023. Results are planned to be submitted for publication in peer-reviewed journals in 2024-2025. CONCLUSIONS This study will quantify immunocompromised individuals’ physical distancing behaviors to avoid COVID-19 and their association with HRQoL as well as health state utilities. INTERNATIONAL REGISTERED REPORT RR1-10.2196/52643

Background Compensation mechanisms and multiplier effects may affect productivity losses due to illness, disability, or premature death of individuals. Hence, they are important in estimating productivity losses and productivity costs in the context of economic evaluations of health interventions. This paper presents a systematic literature review of papers focusing on compensation mechanisms and multiplier effects, as well as whether and how they are included in health economic evaluations. Methods The systematic literature search was performed covering EconLit and PubMed. A data-extraction form was developed focusing on compensation mechanisms and multiplier effects. Results A total of 26 studies were included. Of these, 15 were empirical studies, three studies were methodological studies, two studies combined methodological research with empirical research, four were critical reviews, one study was a critical review combined with methodological research, and one study was a cost–benefit analysis. No uniform definition of compensation mechanisms and multiplier effects was identified. The terminology used to describe compensation mechanisms and multiplier effects varied as well. While the included studies suggest that both multipliers as well as compensation mechanisms substantially impact productivity cost estimates, the available evidence is scarce. Moreover, the generalizability as well as validity of assumptions underlying the calculations are unclear. Available measurement methods for compensation mechanisms and multiplier effects differ in approaches and are hardly validated. Conclusion While our review suggests that compensation mechanisms and multiplier effects may have a significant impact on productivity losses and costs, much remains unclear about their features, valid measurement, and correct valuation. This hampers their current inclusion in economic evaluation, and therefore, more research into both phenomena remains warranted.

Background: The COVID-19 pandemic has a disruptive impact on our society. We therefore conducted a population survey to describe: 1) stress, concerns and quality of life 2) access to healthcare and cancelled/delayed healthcare and 3) productivity during the first 8 weeks of the coronavirus lockdown in the general population. Methods: An online cross-sectional survey was conducted in a representative sample after 8 weeks of the coronavirus lockdown in Belgium and the Netherlands. The survey included a series of three validated questionnaires about quality of life delayed/cancelled medical care and productivity loss using validated questionnaires. Results: In total, 2099 Belgian and 2058 Dutch respondents completed the survey with a mean age of 46.4 and 42.0 years, respectively. Half of the respondents were female in both countries. A small proportion tested positive for COVID-19, 1.4% vs 4.7%, respectively. The majority of respondents with a medical condition was worried about their current health state due to the pandemic (53%) vs (63%), respectively. Respondents experienced postponed/cancelled care (26%) and were concerned about the availability of medication (32%) for both countries. Productivity losses due to the COVID-19 restrictions were calculated in absenteeism (36%) and presenteeism (30%) for Belgium, and (19%) and (35%) for the Netherlands. Most concerns and productivity losses were reported by respondents with children < 12 years, respondents aged 18–35 and respondents with an (expected) COVID-19 infection. Conclusions: This study describes stress, quality of life, medical resource loss and productivity losses in Belgium and the Netherlands after 8 weeks of coronavirus lockdown. The results underline the burden on society.