Patient-reported outcome measures in drugs for neurological conditions approved by European Medicines Agency 2017-2022.

BACKGROUND: Regulatory agencies have been responsive to public demand for inclusion of the patient experience in evaluating and approving therapies. Over the years, patient-reported outcome measures (PROMs) have become increasingly prevalent in clinical trial protocols; however, their influence on regulators, payers, clinicians, and patients' decision-making is not always clear. We recently conducted a cross-sectional study aimed at investigating the use of PROMs in new regulatory approvals of drugs for neurological conditions between 2017 and 2022 in Europe. METHODS: We reviewed European Public Assessment Reports (EPARs) and recorded on a predefined data extraction form whether they considered PROMs, their characteristics (e.g., primary/secondary endpoint, generic/specific instrument) and other relevant information (e.g., therapeutic area, generic/biosimilar, orphan status). Results were tabulated and summarized by means of descriptive statistics. RESULTS: Of the 500 EPARs related to authorized medicines between January 2017 and December 2022, 42 (8%) concerned neurological indications. Among the EPARs of these products, 24 (57%) reported any use of PROMs, typically considered as secondary (38%) endpoints. In total, 100 PROMs were identified, of which the most common were the EQ-5D (9%), the SF-36 (6%), or its shorter adaptation SF-12, the PedsQL (4%). CONCLUSIONS: Compared to other disease areas, neurology is one where the use of patient-reported outcomes evidence is inherently part of the clinical evaluation and for which core outcome sets exist. Better harmonization of the instruments recommended for use would facilitate the consideration of PROMs at all stages in the drug development process.

A scoping review of core outcome sets and their 'mapping' onto real-world data using prostate cancer as a case study.

BACKGROUND: A Core Outcomes Set (COS) is an agreed minimum set of outcomes that should be reported in all clinical studies related to a specific condition. Using prostate cancer as a case study, we identified, summarized, and critically appraised published COS development studies and assessed the degree of overlap between them and selected real-world data (RWD) sources. METHODS: We conducted a scoping review of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database to identify all COS studies developed for prostate cancer. Several characteristics (i.e., study type, methods for consensus, type of participants, outcomes included in COS and corresponding measurement instruments, timing, and sources) were extracted from the studies; outcomes were classified according to a predefined 38-item taxonomy. The study methodology was assessed based on the recent COS-STAndards for Development (COS-STAD) recommendations. A 'mapping' exercise was conducted between the COS identified and RWD routinely collected in selected European countries. RESULTS: Eleven COS development studies published between 1995 and 2017 were retrieved, of which 8 were classified as 'COS for clinical trials and clinical research', 2 as 'COS for practice' and 1 as 'COS patient reported outcomes'. Recommended outcomes were mainly categorized into 'mortality and survival' (17%), 'outcomes related to neoplasm' (18%), and 'renal and urinary outcomes' (13%) with no relevant differences among COS study types. The studies generally fulfilled the criteria for the COS-STAD 'scope specification' domain but not the 'stakeholders involved' and 'consensus process' domains. About 72% overlap existed between COS and linked administrative data sources, with important gaps. Linking with patient registries improved coverage (85%), but was sometimes limited to smaller follow-up patient groups. CONCLUSIONS: This scoping review identified few COS development studies in prostate cancer, some quite dated and with a growing level of methodological quality over time. This study revealed promising overlap between COS and RWD sources, though with important limitations; linking established, national patient registries to administrative data provide the best means to additionally capture patient-reported and some clinical outcomes over time. Thus, increasing the combination of different data sources and the interoperability of systems to follow larger patient groups in RWD is required.

Low socio-economic conditions and prematurity-related morbidities explain healthcare use and costs for 2-year-old very preterm children.

AIM: To estimate healthcare use and related costs for 2-year-old very preterm (VP) children after discharge from the neonatal unit. METHODS: As part of a European project, we recruited an area-based cohort including all VP infants born in three Italian regions (Lazio, Emilia-Romagna and Marche) in 2011-2012. At 2 years corrected age, parents completed a questionnaire on their child health and healthcare use (N = 732, response rate 75.6%). Cost values were assigned based on national reimbursement tariffs. We used multivariable analyses to identify factors associated with any rehospitalisation and overall healthcare costs. RESULTS: The most frequently consulted physicians were the paediatrician (85% of children), the ophthalmologist (36%) and the neurologist/neuropsychiatrist (26%); 38% of children were hospitalised at least once after the initial discharge, for a total of 513 admissions and over one million euros cost, corresponding to 75% of total healthcare costs. Low maternal education and parental occupation index, congenital anomalies and postnatal prematurity-related morbidities significantly increased the risk of rehospitalisation and total healthcare costs. CONCLUSION: Rehospitalisation and outpatient care are frequent in VP children, confirming a substantial health and economic burden. These findings should inform the allocation of resources to preventive and rehabilitation services for these children.

The estimation of health state utility values in rare diseases: overview of existing techniques.

There are several techniques for estimating health state utility values, each of which presents pros and cons in the context of rare diseases (RDs). Direct approaches (e.g. standard gamble and time trade-off) may be too demanding for patients with RDs, since most of them affect young children or cause cognitive impairment. The alternatives are using "vignettes" that describe hypothetical health states for the general public, which may not reflect the heterogeneous manifestations of RDs, or multi-attribute utility instruments (i.e. indirect techniques), such as EQ-5D, which may be less sensitive in capturing the specificities of RDs. The "rule of rescue" approach is a promising alternative in RDs, since it prioritizes identifiable patients with life-threatening or disabling conditions. However, it raises measurement challenges and ethical issues. Furthermore, the literature reports on relevant implications of choosing a technique over others for health technology assessment, which should be considered in relation to individual RDs.

The short-term economic burden of gestational diabetes mellitus in Italy.

BACKGROUND: The incidence of Gestational Diabetes Mellitus (GDM) is rising in all developed countries. This study aimed at assessing the short-term economic burden of GDM from the Italian healthcare system perspective. METHODS: A model was built over the last pregnancy trimester (i.e., from the 28th gestational week until childbirth included). The National Hospital Discharge Database (2014) was accessed to estimate delivery outcome probabilities and inpatient costs in GDM and normal pregnancies (i.e., euglycemia). International Classification of Disease-9th Revision-Clinical Modification (ICD9-CM) diagnostic codes and Diagnosis-Related Group (DRG) codes were used to identify GDM cases and different types of delivery (i.e., vaginal or cesarean) within the database. Neonatal outcomes probabilities were estimated from the literature and included macrosomia, hypoglycemia, hyperbilirubinemia, shoulder dystocia, respiratory distress, and brachial plexus injury. Additional data sources such as regional documents, official price and tariff lists, national statistics and expert opinion were used to populate the model. The average cost per case was calculated at national level to estimate the annual economic burden of GDM. One-way sensitivity analyses and Monte Carlo simulations were performed to quantify the uncertainty around base case results. RESULTS: The amount of pregnancies complicated by GDM in Italy was assessed at 54,783 in 2014 using a prevalence rate of 10.9%. The antenatal outpatient cost per case was estimated at €43.7 in normal pregnancies compared to €370.6 in GDM patients, which is equivalent to a weighted sum of insulin- (14%; €1034.6) and diet- (86%; €262.5) treated women's costs. Inpatient delivery costs were assessed at €1601.6 and €1150.3 for euglycemic women and their infants, and at €1835.0 and €1407.7 for GDM women and their infants, respectively. Thus, the overall cost per case difference between GDM and normal pregnancies was equal to €817.8 (+ 29.2%), resulting in an economic burden of about €44.8 million in 2014 at national level. Probabilistic sensitivity analysis yielded a cost per case difference ranging between €464.9 and €1164.8 in 80% of simulations. CONCLUSIONS: The economic burden of GDM in Italy is substantial even accounting for short-term medical costs only. Future research also addressing long-term consequences from a broader societal perspective is recommended.

Eliciting Preferences for Clinical Follow-Up in Patients with Head and Neck Cancer Using Best-Worst Scaling.

OBJECTIVES: There are no commonly accepted standards for monitoring patients treated for head and neck cancer. The aim of this study was to assess patients' preferences for different aspects of follow-up. METHODS: A best-worst survey was conducted in a sample of head and neck cancer patients in clinical follow-up at the National Cancer Institute (Milan, Italy). Conditional logit regression with choice as the dependent variable was run to analyse the data. A covariate-adjusted analysis was performed in order to identify socio-demographic and clinical factors related to the selection of best-worst items. The participants were asked to report any difficulties encountered during the survey. RESULTS: A total of 143 patients, predominantly male (74%) and with a mean age of 58 years were enrolled in the survey. The strongest positive preference was expressed for a hospital-based program of physical examinations with frequency decreasing over time. Conversely, the lowest valued item was not performing any positron emission tomography (PET) scan during follow-up. Patients with high educational levels were more likely to value attending a primary care-based program and undergoing intensive radiological investigations. Other patient-specific variables significantly associated with the choice of items were employment and living status, time already spent in follow-up and number of treatments received. CONCLUSIONS: Overall, patients were more likely to choose an intensive follow-up scheme broadly consistent with the program currently administered by the hospital. There is little evidence of preference heterogeneity that might justify customized programs based on demographics. The best-worst scaling task appeared feasible for most participants.

A systematic literature review of health state utility values in head and neck cancer.

BACKGROUND: Health state utility values (HSUVs) are essential parameters in model-based economic evaluations. This study systematically identifies HSUVs in head and neck cancer and provides guidance for selecting them from a growing body of health-related quality of life studies. METHODS: We systematically reviewed the published literature by searching PubMed, EMBASE and The Cochrane Library using a pre-defined combination of keywords. The Tufts Cost-Effectiveness Analysis Registry and the School of Health and Related Research Health Utilities Database (ScHARRHUD) specifically containing health utilities were also queried, in addition to the Health Economics Research Centre database of mapping studies. Studies were considered for inclusion if reporting original HSUVs assessed using established techniques. The characteristics of each study including country, design, sample size, cancer subsite addressed and demographics of responders were summarized narratively using a data extraction form. Quality scoring and critical appraisal of the included studies were performed based on published recommendations. RESULTS: Of a total 1048 records identified by the search, 28 studies qualified for data extraction and 346 unique HSUVs were retrieved from them. HSUVs were estimated using direct methods (e.g. standard gamble; n = 10 studies), multi-attribute utility instruments (MAUIs; n = 13) and mapping techniques (n = 3); two studies adopted both direct and indirect approaches. Within the MAUIs, the EuroQol 5-dimension questionnaire (EQ-5D) was the most frequently used (n = 11), followed by the Health Utility Index Mark 3 (HUI3; n = 2), the 15D (n = 2) and the Short Form-Six Dimension (SF-6D; n = 1). Different methods and types of responders (i.e. patients, healthy subjects, clinical experts) influenced the magnitude of HSUVs for comparable health states. Only one mapping study developed an original algorithm using head and neck cancer data. The identified studies were considered of intermediate quality. DISCUSSION: This review provides a dataset of HSUVs systematically retrieved from published studies in head and neck cancer. There is currently a lack of research for some disease phases including recurrent and metastatic cancer, and treatment-related complications. In selecting HSUVs for cost-effectiveness modeling purposes, preference should be given to EQ-5D utility values; however, mapping to EQ-5D is a potentially valuable technique that should be further developed in this cancer population.

Behind the Scenes: A Qualitative Investigation of Interviewers' Performance in EQ-5D Valuation Studies.

BACKGROUND: The EuroQol Valuation Technology (EQ-VT) protocol is currently employed by the valuation studies of the EQ family of instruments worldwide. To date, all the evidence in support of the quality control (QC) originates from quantitative indicators. OBJECTIVE: We aimed to explore interviewers' conversational patterns in EQ-VT interviews, beyond quantitative QC indicators, and to provide a preliminary exploration of how the interaction between interviewer and respondent impacts data quality. METHODS: Two researchers transcribed and independently coded 24 video-recorded interviews from the Italian EQ-5D-5L valuation study, adopting the conversational analysis framework. The analysis identified positive and negative 'patterns' of conversational practice. These were categorized into themes and sub-themes and were used to score a random sample of 42 video-recorded interviews conducted at different time points by seven interviewers. RESULTS: The conversational analysis identified 20 positive and 14 negative interview patterns, which were grouped into two main themes (i.e., task execution and communication skills). Positive items included appending questions that stimulated respondents' engagement, providing different explanations for an unclear aspect, supporting the participant with useful information for completing the tasks, and increasing the interview's coherence by confirming the respondent answers. Negative patterns included moving forward in the exercise without making sure that the respondent understood, trying to force an answer from the respondent, speaking too fast, and providing incomplete or incorrect explanations of the task. Most interviewers exhibited a moderate increase in positive patterns or a decrease in negative patterns over time. A certain degree of consistency between the quantitative QC results and the qualitative scoring deriving from the interviewer-respondent interaction was observed, with the best and worst performers of the qualitative scoring showing good and bad scores on key QC items, respectively. CONCLUSIONS: The identified positive and negative patterns may be useful to inform the training material of EQ-VT studies worldwide and complement the existing QC process.

The development of an archive of patient-reported outcome measures (PROMs) in oncology: The Italian PRO4All project.

BACKGROUND: Choosing the most adequate measure of patient-reported outcomes (PROs) for a specific medical condition is not straightforward. This study aimed to develop a comprehensive archive of patient-reported outcome measures (PROMs), observer-reported outcome measures (ObsROMs) and caregiver-reported outcome measures (CROMs) in oncology and identify their main characteristics and target outcome domains. MATERIALS AND METHODS: As part of the Italian PRO4All Project, we retrieved questionnaires through an extensive search of online databases. We developed a data extraction form to collect information on cancer type, questionnaire variant(s), recall period, and scoring system. We performed a content analysis of the questionnaires to assign each item a specific outcome domain according to a predefined 38-item taxonomy. RESULTS: A total of 386 PROMs (n = 356), ObsROMs (n = 13) and CROMs (n = 17) were identified and described; of these, 358 were also analyzed in their content. 47.3 % of the instruments were cancer type-specific, 45.1 % were generic for cancer and 7.9 % were developed for the general population but also recommended in oncology. The great majority (92.2 %) were patient-reported. In 50.3 % the recall period was "last week". The mean number of items per questionnaire was 22.0 (range: 1-130). 7794 items were assigned an outcome domain, the most frequent being emotional functioning/wellbeing (22 %), physical functioning (15.7 %), general outcomes (10.1 %) and delivery of care (8.9 %). CONCLUSIONS: There are a variety of patient and caregiver-reported measures in oncology. This archive can guide researchers and practitioners in selecting the most suitable measures and fostering a patient-centered approach in clinical trials, clinical practice, and regulatory activities.

Quality Appraisal in Systematic Literature Reviews of Studies Eliciting Health State Utility Values: Conceptual Considerations.

BACKGROUND: The increasing number of studies that generate health state utility values (HSUVs) and the impact of HSUVs on cost-utility analyses make a robust tailored quality appraisal (QA) tool for systematic reviews of these studies necessary. OBJECTIVE: This study aimed to address conceptual issues regarding QA in systematic reviews of studies eliciting HSUVs by establishing a consensus on the definitions, dimensions and scope of a QA tool specific to this context. METHODS: A modified Delphi method was used in this study. An international multidisciplinary panel of seven experts was purposively assembled. The experts engaged in two anonymous online survey rounds. After each round, the experts received structured and controlled feedback on the previous phase. Controlled feedback allowed the experts to re-evaluate and adjust their positions based on collective insights. Following these surveys, a virtual face-to-face meeting was held to resolve outstanding issues. Consensus was defined a priori at all stages of the modified Delphi process. RESULTS: The response rates to the first-round and second-round questionnaires and the virtual consensus meeting were 100%, 86% and 71%, respectively. The entire process culminated in a consensus on the definitions of scientific quality, QA, the three QA dimensions-reporting, relevance and  methodological quality-and the scope of a QA tool specific to studies that elicit HSUVs. CONCLUSIONS: Achieving this consensus marks a pivotal step towards developing a QA tool specific to systematic reviews of studies eliciting HSUVs. Future research will build on this foundation, identify QA items, signalling questions and response options, and develop a QA tool specific to studies eliciting HSUVs.

The estimation of health state utility values in rare diseases: do the approaches in submissions for NICE technology appraisals reflect the existing literature? A scoping review.

BACKGROUND: Rare diseases negatively impact patients' quality of life, but the estimation of health state utility values (HSUVs) in research studies and cost-utility models for health technology assessment is challenging. OBJECTIVES: This study compared the methods for estimating the HSUVs included in manufacturers' submissions of orphan drugs to the National Institute for Health and Care Excellence (NICE) with those of published studies addressing the same rare diseases to understand whether manufacturers fully exploited the existing literature in developing their economic models. METHODS: All NICE Technology Appraisal (TA) and Highly Specialized Technologies (HST) guidance documents of non-cancer European Medicines Agency (EMA) orphan medicinal products were reviewed and compared with any published primary studies, retrieved via PubMed until November 2020, and estimating HSUVs for the same conditions addressed in manufacturers' submissions. RESULTS: We identified 22 NICE TA/HST appraisal reports addressing 19 different rare diseases. Sixteen reports presented original HSUVs estimated using EQ-5D or Health Utility Index (n = 12), direct methods (n = 2) or mapping (n = 2), while the other six included values obtained from the literature only. In parallel, we identified 111 published studies: 86.6% used preference-based measures (mainly EQ-5D, 60.7%), 12.5% direct techniques, and 2.7% mapping. The collection of values from non-patient populations (using 'vignettes') was more frequent in manufacturers' submissions than in the literature (22.7% vs. 8.0%). CONCLUSIONS: The agreement on methodological choices between manufacturers' submissions and published literature was only partial. More efforts should be made by manufacturers to accurately reflect the academic literature and its methodological recommendations in orphan drugs submissions.

The Assessment of Patient-Reported Outcomes for the Authorisation of Medicines in Europe: A Review of European Public Assessment Reports from 2017 to 2022.

OBJECTIVES: Health regulators have progressively increased their attention and focus on patient-reported outcomes (PROs), driven by the diffusion of a patient-centred approach to the drug development process. This study investigates the consideration of PROs and their measures (PROMs) in the authorisation of medicines in Europe. METHODS: All medicines for human use authorised or refused by the European Medicines Agency (EMA) in the period 2017-2022 were identified, and corresponding European Public Assessment Reports (EPARs) were downloaded for review. Medicine and PROs/PROM characteristics were systematically recorded. A multivariate logistic regression was performed to identify variables associated with the use of patient-reported evidence in EPARs. RESULTS: Overall, 497 EPARs of authorised medicines and 19 EPARs of refused medicines were analysed; of these, 240 (48.3%) and 10 (52.6%), respectively, reported any use of PROs/PROMs (p = 0.710). For authorised medicines, the likelihood of using PROs/PROMs was negatively affected by generic (OR = 0.01, p < 0.001) and biosimilar status (OR = 0.46, p = 0.013) and positively affected by orphan status (OR = 1.41, p = 0.177). The use of PROMs (50.6% in 2017 vs 47.9% in 2022) did not show a clear pattern over the 6-year period considered (p = 0.758) and was particularly uncommon in some therapeutic areas (e.g., 15.2% in infectious diseases). A total of 816 dyads of PROs/PROMs were identified. On average each EPAR considered 1.6 (range: 0-14) instruments. Patient-reported outcomes were typically secondary (53.3%) and exploratory endpoints (18.8%); in one-third of cases (32.5%), they assessed generic quality of life. Among the PROMs, 227 (27.8%) targeted general population; EQ-5D (11.0%), SF-36/SF-12 (5.9%) and EORTC QLQ-C30 (5.6%) were the instruments most frequently used. CONCLUSIONS: This study suggests PROs/PROMs are considered in less than half of total medicine assessments and even more rarely in some disease areas. The adoption of PROs is key in EMA strategy to 2025 and would be facilitated by consensus development on their measures and optimisation of data collection.

EQ-5D-5L Population Norms for Italy.

OBJECTIVES: This study aimed to provide normative data obtained in response to the EQ-5D-5L questionnaire in Italy and compare this with data from other countries. METHODS: A sample of the Italian adult population (aged ≥ 18 years) was recruited and interviewed online using videoconferencing software (Zoom) between November 2020 and February 2021. The distribution of answers was estimated as per the descriptive system of the EQ-5D-5L, and descriptive statistics were calculated for the EQ VAS score and EQ-5D-5L index value in the whole sample and relevant subgroups. An ordinary least square (OLS) regression was performed to evaluate the impact of sociodemographic variables on EQ-5D-5L results. Lastly, a comparison was made with EQ-5D-5L population norms of other countries. Data analysis was performed using Microsoft Excel and Stata 13. RESULTS: Overall, 1182 people representative of the Italian population (2020) in terms of sex and geographical area responded to the survey. Of the 3125 potential EQ-5D-5L health states, only 106 (3.4%) were selected, and the '11111' and '11112' states were chosen by half of the participants. In terms of EQ-5D-5L dimensions, the frequency of any problems (from slight to extreme) associated with anxiety and depression was high among the very young (18-24 years, 56.0%) and in women of all ages (49.7%). The mean index value (± standard deviation [SD]) was 0.93 (± 0.11) for the entire sample and gradually decreased with age, moving from 0.95 (± 0.06) in the youngest group (18-24 years) to 0.91 (± 0.13) in the oldest age group (≥ 75 years). Similarly, the mean EQ VAS score (± SD) was 81.8 (± 13.5), and decreased from 87.0 (± 8.9) in the 18-24 years age group to 75.1 (± 16.4) among participants > 75 years of age. The existence of self-reported chronic conditions (e.g., cardiovascular disease), female sex, and social assistance recipiency were negatively associated with the EQ-5D index value, while the EQ VAS score was significantly lower in people with chronic conditions and aged > 55 years. Conversely, higher income levels had a positive impact on both the EQ-5D index value and the EQ VAS score. Lastly, both the EQ-5D index value and EQ VAS score in Italy were, on average, higher than in most European countries. CONCLUSIONS: EQ-5D-5L population norms provide useful insights into the health status of the Italian population and can be used as a reference for other surveys using the same instrument.

Collecting Physicians' Preferences on Medical Devices: Are We Doing It Right? Evidence from Italian Orthopedists Using 2 Different Stated Preference Methods.

OBJECTIVES: Physician preference items (PPIs) are high-cost medical devices for which clinicians express firm preferences with respect to a particular manufacturer or product. This study aims to identify the most important factors in the choice of new PPIs (hip or knee prosthesis) and infer about the existence of possible response biases in using 2 alternative stated preference techniques. METHODS: Six key attributes with 3 levels each were identified based on a literature review and clinical experts' opinions. An online survey was administered to Italian hospital orthopedists using type 1 best-worst scaling (BWS) and binary discrete choice experiment (DCE). BWS data were analyzed through descriptive statistics and conditional logit model. A mixed logit regression model was applied to DCE data, and willingness-to-pay (WTP) was estimated. All analyses were conducted using Stata 16. RESULTS: A sample of 108 orthopedists were enrolled. In BWS, the most important attribute was "clinical evidence," followed by "quality of products," while the least relevant items were "relationship with the sales representative" and "cost." DCE results suggested instead that orthopedists prefer high-quality products with robust clinical evidence, positive health technology assessment recommendation and affordable cost, and for which they have a consolidated experience of use and a good relationship with the sales representative. CONCLUSIONS: The elicitation of preferences for PPIs using alternative methods can lead to different results. The BWS of type 1, which is similar to a ranking exercise, seems to be more affected by acquiescent responding and social desirability than the DCE, which introduces tradeoffs in the choice task and is likely to reveal more about true preferences. HIGHLIGHTS: Physician preference items (PPIs) are medical devices particularly exposed to physicians' choice with regard to type of product and supplier.Some established techniques of collecting preferences can be affected by response biases such as acquiescent responding and social desirability.Discrete choice experiments, introducing more complex tradeoffs in the choice task, are likely to mitigate such biases and reveal true physicians' preferences for PPIs.

Improving Interpretation of Evidence Relating to Quality of Life in Health Technology Assessments of Rare Disease Treatments.

Rare diseases are often severe, debilitating, life-limiting conditions, many of which occur in childhood. These complex conditions have a wide range of clinical manifestations that have a substantial impact on the lives of patients, carers and families and often produce heterogeneous clinical outcomes. Therefore, the evaluation of quality-of-life (QoL) impacts is important. In health technology assessment (HTA), patient-reported outcome measures (PROMs) and/or health state utility values (HSUVs) are used to determine QoL impacts of new treatments, but their use in rare diseases is challenging due to small and heterogeneous populations and limited disease knowledge. This paper describes challenges associated with the use of patient-reported outcomes (PROs)/HSUVs to evaluate QoL in HTA of rare disease treatments (RDTs) and identifies five recommendations to ensure appropriate interpretation of QoL impacts. These were derived from mixed methods research (literature reviews, appraisal document analyses, appraisal committee observations and interviews) examining the use of PROs/HSUVs in HTA of RDTs. They highlight that HTAs of RDTs must (1) understand the QoL impacts of the disease and of treatments; (2) critically assess PRO data, recognising the nuances in development and administration of PROMs/HSUVs, considering what is feasible and what matters most to the patient population; (3) recognise that lack of significant effect on a PRO does not imply no QoL benefit; (4) use different forms of evidence to understand QoL impacts, such as patient input; and (5) provide methodological guidance to capture QoL impacts on patients/carers.

Feasibility of Deriving Health State Utilities in Mycosis Fungoides Cutaneous T-Cell Lymphoma Using Mapping Algorithms.

BACKGROUND: A prospective, observational, US-based study (PROVe) used three questionnaires (Pruritus-VAS, Skindex-29, MF/SS-CTCL QoL) to assess quality of life in patients diagnosed with mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL); however, none of these studies was provided with a preference-based algorithm yielding health state utility values (HSUVs). OBJECTIVE: This study aimed to assess the feasibility of deriving HSUVs from published mapping algorithms by comparing mapped utilities with the HSUVs reported in the MF-CTCL literature. METHODS: We searched PubMed, the School of Health and Related Research Health Utility Database (ScHARRHUD), and the Health Economics Research Centre (HERC) database of mapping studies (version 7.0) to identify any studies mapping Pruritus-VAS, Skindex-29, or MF/SS-CTCL QoL to a preference-based instrument (ideally, EQ-5D), and any studies assessing HSUVs in MF-CTCL. Two algorithms from a recent study that mapped Pruritus-VAS onto EQ-5D-3L were applied to the PROVe patient-level data. We performed multiple imputation to handle missing VAS data, calculated average mapped utilities in the whole sample, and compared them with relevant factors using the t-test and one-way analysis of variance (ANOVA). RESULTS: Overall, 298 patients provided 1441 Pruritus-VAS scores over a 2-year follow-up (1-21 visits per patient). The average mapped HSUVs ranged between 0.950 and 0.999 depending on the algorithm applied and imputation of missing data. In subgroup analysis, significant differences (p < 0.05) were observed according to age, race, and cancer stage. A few previous studies that collected HSUVs from MF-CTCL patients reported mean values of between 0.82 and 0.87 using time trade-off, 0.63 and 0.83 using EQ-5D, and 0.51 and 0.69 using the HUI3. CONCLUSIONS: The HSUVs derived by applying published mapping algorithms to PROVe Pruritus-VAS data appeared largely overestimated if compared with the existing literature. More research is required to understand the applicability of existing mapping algorithms and to develop new mapping algorithms in MF-CTCL.

An EQ-5D-5L value set for Italy using videoconferencing interviews and feasibility of a new mode of administration.

OBJECTIVES: To test the feasibility of using videoconferencing (VC) administered interviews and to derive an EQ-5D-5L value set for Italy. METHODS: Preferences were collected using the EuroQol standardized valuation protocol (EQ-VT) administered via VC. Two valuation methods were employed, composite time trade-off (cTTO) and discrete choice experiment (DCE). Technical, organizational and protocol feasibility were tested in a pilot of 198 interviews. Upon positive assessment, data collection continued with a target sample of 1000-1200 participants including the pilot. Quality control (QC) procedures were employed to monitor interviewers' performance during the pilot and the data collection. Data were modelled using GLS, Tobit, Logit and Hybrid models with different error specifications. Monotonicity of coefficients, statistical significance, and theoretical considerations informed the model choice. RESULTS: Dropouts and technical problems occurred in less than 5% of the 198 pilot interviews. Protocol compliance was demonstrated with significant improvements in QC parameters and limited interviewers' effects, for all interviewers. Overall, interviewers were satisfied with this mode of administration, highlighting it allows flexibility and efficient scheduling. Based on these results, VC was deemed as a feasible mode of administration. The study collected preferences for 1182 responders, including the pilot interviews. The demographic characteristics of the sample were representative of the Italian general population for age, gender and geographical macro-areas. The hybrid Tobit heteroscedastic model without constant estimated on the full sample (including pilot) was selected for the derivation of the value set. Values ranged from -0.571 for the worst health state (55555) to 1 for the best health state (11111). Pain/discomfort registered the largest decrement, followed by mobility, anxiety/depression, self-care, and usual activities. 523 health states were worse than dead. CONCLUSIONS: VC is viable for the conduct of valuation interviews. The Italian value set for the EQ-5D-5L can be used for value determinations of health technologies.

Consideration of quality of life in the health technology assessments of rare disease treatments.

OBJECTIVES: Challenges with patient-reported outcome (PRO) evidence and health state utility values (HSUVs) in rare diseases exist due to small, heterogeneous populations, lack of disease knowledge and early onset. To better incorporate quality of life (QoL) into Health Technology Assessment, a clearer understanding of these challenges is needed. METHODS: NICE appraisals of non-oncology treatments with an EMA orphan designation (n = 24), and corresponding appraisals in the Netherlands, France, and Germany were included. Document analysis of appraisal reports investigated how PROs/HSUVs influenced decision-making and was representative of QoL impact of condition and treatment. RESULTS: PRO evidence was not included in 6/24 NICE appraisals. When included, it either failed to demonstrate change, capture domains important for patients, or was uncertain. In the other countries, little information was reported and evidence largely did not demonstrate change. In NICE appraisals, HSUVs were derived through the collection of EQ-5D data (7/24 cases), mapping (6/24), vignettes (5/24), and published literature or other techniques (6/24). The majority did not use data collected alongside clinical trials. Few measures demonstrated significant change due to lack of sensitivity or face validity, short-term data, or implausible health states. In 8/24 NICE appraisals, patient surveys or input during appraisal committee meetings supported the interpretation of uncertainty or provided evidence about QoL. CONCLUSIONS: This study sheds light on the nature of PRO evidence in rare diseases and associated challenges. Results emphasise the need for improved development and use of PRO/HSUVs. Other forms of evidence and expert input are crucial to support better appraisal of uncertain or missing evidence.

Italy: Health System Review.

This analysis of the Italian health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. Italy has a regionalized National Health Service (SSN) that provides universal coverage largely free of charge at the point of delivery, though certain services and goods require a co-payment. Life expectancy in Italy is historically among the highest in the EU. However, regional differences in health indicators are marked, as well as in per capita spending, distribution of health professionals and in the quality of health services. Overall, Italy's health spending per capita is lower than the EU average and is among the lowest in western European countries. Private spending has increased in recent years, although this trend was halted in 2020 during the coronavirus disease 2019 (COVID-19) pandemic. A key focus of health policies in recent decades was to promote a shift away from unnecessary inpatient care, with a considerable reduction of acute hospital beds and stagnating overall growth in health personnel. However, this was not counterbalanced by a sufficient strengthening of community services in order to cope with the ageing population's needs and related chronic conditions burden. This had important repercussions during the COVID-19 emergency, as the health system felt the impact of previous reductions in hospital beds and capacity and underinvestment in community-based care. Reorganizing hospital and community care will require a strong alignment between central and regional authorities. The COVID-19 crisis also highlighted several issues pre-dating the pandemic that need to be addressed to improve the sustainability and resilience of the SSN. The main outstanding challenges for the health system are linked to addressing historic underinvestment in the health workforce, modernizing outdated infrastructure and equipment, and enhancing information infrastructure. Italy's National Recovery and Resilience Plan, underwritten by the Next Generation EU budget to assist with economic recovery from the COVID-19 pandemic, contains specific health sector priorities, such as strengthening the country's primary and community care, boosting capital investment and funding the digitalization of the health care system.

The Use of Patient-Reported Outcome Measures in Rare Diseases and Implications for Health Technology Assessment.

BACKGROUND: Patient-reported outcome measures (PROMs) are used in health technology assessment (HTA) to measure patient experiences with disease and treatment, allowing a deeper understanding of treatment impact beyond clinical endpoints. Developing and administering PROMs for rare diseases poses unique challenges because of small patient populations, disease heterogeneity, lack of natural history knowledge, and short-term studies. OBJECTIVE: This research aims to identify key factors to consider when using different types of PROMs in HTA for rare disease treatments (RDTs). METHODS: A scoping review of scientific and grey literature was conducted, with no date or publication type restrictions. Information on the advantages of and the challenges and potential solutions when using different types of PROMs for RDTs, including psychometric properties, was extracted and synthesized. RESULTS: Of 79 records from PubMed, 32 were included, plus 12 records from the grey literature. PROMs for rare diseases face potential data collection and psychometric challenges resulting from small patient populations and disease heterogeneity. Generic PROMs are comparable across diseases but not sensitive to disease specificities. Disease-specific instruments are sensitive but do not exist for many rare diseases and rarely provide the utility values required by some HTA bodies. Creating new PROMs is time and resource intensive. Potential solutions include pooling data (multi-site/international data collection), using computer-assisted technology, or using generic and disease-specific PROMs in a complementary way. CONCLUSIONS: PROMs are relevant in HTA for RDTs but pose a number of difficulties. A deeper understanding of the potential advantages of and the challenges and potential solutions for each can help manage these difficulties.