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.

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.

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.

Implementing Outcomes-Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel.

BACKGROUND AND OBJECTIVE: Enthusiasm for the use of outcomes-based managed entry agreements (OBMEAs) to manage uncertainties apparent at the time of appraisal/pricing and reimbursement of new medicines has waned over the past decade, as challenges in establishment, implementation and re-appraisal have been identified. With the recent advent of innovative treatments for rare diseases that have uncertainties in the clinical evidence base, but which could meet a high unmet need, there has been renewed interest in the potential of OBMEAs. The objective of this research was to review the implementation of OBMEAs for two case studies across countries in the European Union, Australia and Canada, to identify good practices that could inform development of tools to support implementation of OBMEAs. METHODS: To investigate how OBMEAs are being implemented with rare disease treatments, we collected information from health technology assessment/payer experts in countries that had implemented OBMEAs for either nusinersen in spinal muscular atrophy or tisagenlecleucel in two cancer indications. Operational characteristics of the OBMEAs that were publicly available were documented. Then, the experts discussed issues in implementing these OBMEAs and specific approaches taken to overcome challenges. RESULTS: The OBMEAs identified were based on individual outcomes to ensure appropriate use, manage continuation of treatment and in two cases linked to payment schedules, or they were population based, coverage with evidence development. For nusinersen, population-based OBMEAs are documented in Belgium, England and the Netherlands and individual-based schemes in Bulgaria, Ireland, Italy and Lithuania. For tisagenlecleucel, there were population-based schemes in Australia, Belgium, England and France and individual-based schemes in Italy and Spain. Comparison of the OBMEA constructs showed some clear published frameworks and clarity of the uncertainties to be addressed that were similar across countries. Agreements were generally made between the marketing authorisation holder and the payer with involvement of expert physicians. Only England and the Netherlands involved patients. Italy used its long-established, national, web-based, treatment-specific data collection system linked to reimbursement and Spain has just developed such a national treatment registry system. Other countries relied on a variety of data collection systems (including clinical registries) and administrative data. Durations of agreements varied for these treatments as did processes for interim reporting. The processes to ensure data quality, completeness and sufficiency for re-analysis after coverage with evidence development were not always clear, neither were analysis plans. CONCLUSIONS: These case studies have shown that important information about the constructs of OBMEAs for rare disease treatments are publicly available, and for some jurisdictions, interim reports of progress. Outcomes-based managed entry agreements can play an important role not only in reimbursement, but also in treatment optimisation. However, they are complex to implement and should be the exception and not the rule. More recent OBMEAs have developed document covenants among stakeholders or electronic systems to provide assurances about data sufficiency. For coverage with evidence development, there is an opportunity for greater collaboration among jurisdictions to share processes, develop common data collection agreements, and share interim and final reports. The establishment of an international public portal to host such reports would be particularly valuable for rare disease treatments.

Examining the impact of different country processes for appraising rare disease treatments: a case study analysis.

BACKGROUND: Conventional appraisal and reimbursement processes are being challenged by the increasing number of rare disease treatments (RDTs) with a small evidence base and often a high price. Processes to appraise RDTs vary across countries; some use standard processes, others have separate processes or adapted processes that explicitly deal with rare disease specificities. The objective of this study was to examine the impacts of different appraisal processes for two RDTs. METHODS: A case study analysis was conducted using countries with different forms of appraisal processes for RDTs for which public health technology assessment (HTA) reports were available. Two contrasting RDTs were chosen according to the criteria: rare versus ultra-rare treatment, affecting child versus adult, life-threatening versus disabling. Information from public HTA reports for each country's RDT appraisal was extracted into templates, allowing a systematic comparison of the appraisals across countries and identification of the impact of the different processes in practice. RESULTS: Reports from Belgium, England, France, Germany, Italy, Netherlands, Norway, Scotland, Sweden, and the USA were selected for nusinersen (for spinal muscular atrophy) and voretigene neparvovec (for inherited retinal disorders). Countries with separate or adapted processes had more consistent approaches for managing RDT-related issues during appraisal, such as stakeholder involvement and criteria to address the specificities of RDTs, creating more transparency in decision-making. CONCLUSIONS: Findings suggest that separate or adapted approaches for RDT appraisal may facilitate more structured, consistent decision-making and better management of RDT specificities.

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.

Price and reimbursement for orphan medicines and managed entry agreements: does Italy need a framework?

This article illustrates a consensus opinion of an expert panel on the need and usefulness of a framework for price and reimbursement (P&R) process and managed entry agreements (MEAs) for orphan medicines in Italy. This opinion was gathered in three rounds: an introductory document was sent to the panel and discussed during a recorded online meeting. A second document was sent to the panel for their review. In the third step the final document was validated. Members of the expert panel are the authors of the article. The panel agreed that Italy does not need a specific value framework for orphan medicines, driving the P&R process. Rather, a more structured value framework for all medicines tailored to the specific drugs can be useful. For orphan drugs, the panel advocated for a multidisciplinary approach and the contribution of different stakeholders to value assessment, and acknowledged the importance of addressing, more than for other drugs, unmet needs, equity issues and societal value. The panel raised the need of increasing the importance of patient-reported outcomes. Experts, acknowledging the growing criticisms in implementation of outcome-based agreements in Italy, expressed their position against their abandonment in favour of discounts only and supported orphan medicines as natural candidates for these agreements. Finally, the panel made some recommendations on the appraisal process for orphan medicines, including an early discussion on the uncertainty of the evidence generated and the adoption of a structured approach to identify the agreement, which better responds to the uncertainty.

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.

Are supplemental appraisal/reimbursement processes needed for rare disease treatments? An international comparison of country approaches.

BACKGROUND: There is increasing recognition that conventional appraisal approaches may be unsuitable for assessing the value rare disease treatments (RDTs). This research examines what supplemental appraisal/reimbursement processes for RDTs are used internationally and how they can be characterised. A qualitative research design was used that included (1) documentation of country appraisal/reimbursement processes for RDTs via questionnaires, desk research and iterative interactions with country experts to produce country vignettes, and (2) a cross-country analysis of these processes to identify and characterise features in supplemental processes for RDTs, and compare them to countries without supplemental processes. RESULTS: Thirty-two of the 37 invited countries participated in this research. Forty-one percent (13/32) use supplemental processes for RDTs. Their level of integration within standard processes ranged from low to high, characterised by whether they are separate or partially separate from the standard process, adapted or accelerated standard processes, or standard processes that may be applied to RDTs. They are characterised by features implemented throughout the appraisal process. These features are mechanisms that allow application of different standards to assess the value of the medicine, support to the appraisal/decision-making process, overcome the issues of lack of cost-effectiveness, or exempt from part of/the full appraisal/reimbursement process. They increase the likelihood of reimbursement by adjusting and/or foregoing part of the assessment process, or accepting to pay more for the same added benefit as for common conditions. A large proportion of countries with standard processes include one or more of these features (formally or informally) or are discussing potential changes in their systems. CONCLUSIONS: Results suggest revealed preferences to treat RDTs differently than conventional medicines. Some of the challenges around uncertainty and high price remain, but supplemental process features can support decision-making that is more flexible and consistent. Many of these processes are new and countries continue to adjust as they gain experience.

'Mapping' Health State Utility Values from Non-preference-Based Measures: A Systematic Literature Review in Rare Diseases.

BACKGROUND: The use of patient-reported outcome measures (PROMs) to monitor the effects of disease and treatment on patient symptomatology and daily life is increasing in rare diseases (RDs) (i.e. those affecting less than one in 2000 people); however, these instruments seldom yield health state utility values (HSUVs) for cost-utility analyses. In such a context, 'mapping' allows HSUVs to be obtained by establishing a statistical relationship between a 'source' (e.g. a disease-specific PROM) and a 'target' preference-based measure [e.g. the EuroQol-5 Dimension (EQ-5D) tool]. OBJECTIVE: This study aimed to systematically review all published studies using 'mapping' to derive HSUVs from non-preference-based measures in RDs, and identify any critical issues related to the main features of RDs, which are characterised by small, heterogeneous, and geographically dispersed patient populations. METHODS: The following databases were searched during the first half of 2019 without time, study design, or language restrictions: MEDLINE (via 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). The keywords combined terms related to 'mapping' with Orphanet's list of RD indications (e.g. 'acromegaly') in addition to 'rare' and 'orphan'. 'Very rare' diseases (i.e. those with fewer than 1000 cases or families documented in the medical literature) were excluded from the searches. A predefined, pilot-tested extraction template (in Excel®) was used to collect structured information from the studies. RESULTS: Two groups of studies were identified in the review. The first group (n = 19) developed novel mapping algorithms in 13 different RDs. As a target measure, the majority used EQ-5D, and the others used the Short-Form Six-Dimension (SF-6D) and 15D; most studies adopted ordinary least squares (OLS) regression. The second group of studies (n = 9) applied previously published algorithms in non-RDs to comparable RDs, mainly in the field of cancer. The critical issues relating to 'mapping' in RDs included the availability of very few studies, the relatively high number of cancer studies, and the absence of research in paediatric RDs. Moreover, the reviewed studies recruited small samples, showed a limited overlap between RD-specific and generic PROMs, and highlighted the presence of cultural and linguistic factors influencing results in multi-country studies. Lastly, the application of existing algorithms developed in non-RDs tended to produce inaccuracies at the bottom of the EQ-5D scale, due to the greater severity of RDs. CONCLUSIONS: More research is encouraged to develop algorithms for a broader spectrum of RDs (including those affecting young children), improve mapping study quality, test the generalisability of algorithms developed in non-RDs (e.g. HIV) to rare variants or evolutions of the same condition (e.g. AIDS wasting syndrome), and verify the robustness of results when mapped HSUVs are used in cost-utility models.

Why do health technology assessment drug reimbursement recommendations differ between countries? A parallel convergent mixed methods study.

Using quantitative and qualitative research designs, respectively, two studies investigated why countries make different health technology assessment (HTA) drug reimbursement recommendations. Building on these, the objective of this study was to (a) develop a conceptual framework integrating the factors explaining these decisions, (b) explore their relationship and (c) assess if they are congruent, complementary or discrepant. A parallel convergent mixed methods design was used. Countries included in both previous studies were selected (England, Sweden, Scotland and France). A conceptual framework that integrated and organised the factors explaining the decisions from the two studies was developed. Relationships between factors were explored and illustrated through case studies. The framework distinguishes macro-level factors from micro-level ones. Only two of the factors common to both studies were congruent, while two others reached discrepant conclusions (stakeholder input and external review of the evidence processes). The remaining factors identified within one or both studies were complementary. Bringing together these findings contributed to generating a more complete picture of why countries make different HTA recommendations. Results were mostly complementary, explaining and enhancing each other. We conclude that differences often result from a combination of factors, with an important component relating to what occurs during the deliberative process.

Lung Cancer App (LuCApp) study protocol: a randomised controlled trial to evaluate a mobile supportive care app for patients with metastatic lung cancer.

INTRODUCTION: Mobile health technologies may enhance patient empowerment and data integration along the whole care continuum. However, these interventions pose relatively new regulatory, organisational and technological challenges that limit appropriate evaluation. Lung Cancer App (LuCApp) is a mobile application developed by researchers and clinicians to promote real-time monitoring and management of patients' symptoms. This protocol illustrates a clinical trial designed to evaluate the usability, effectiveness and cost-effectiveness of LuCApp versus standard of care. METHODS AND ANALYSIS: This is a 24-week two-arm non-blinded multicentre parallel randomised controlled trial. A total of 120 adult patients diagnosed with small or non-small cell lung cancer and eligible for pharmaceutical treatments will be allocated 1:1 to receiving either standard care or LuCApp in addition to standard care at three oncology sites in Northern Italy. During the treatment period, LuCApp allows daily monitoring and grading of a list of symptoms, which trigger alerts to the physicians in case predefined severity thresholds are met. Patients will complete a baseline assessment and a set of valid and reliable patient-reported outcome measures every 3±1 weeks, and up to 24 weeks. The primary outcome is the change in the score of the Trial Outcome Index in the Functional Assessment of Cancer Therapy (Lung) questionnaire from baseline to 12 weeks. Secondary outcomes are the Lung Cancer Subscale, the EuroQoL 5D-5L questionnaire, the Hospital Anxiety and Depression Scale, the Supportive Care Needs Survey Short Form, the app usability questionnaire and the Zarit Burden Interview for the main caregiver. ETHICS AND DISSEMINATION: The trial received ethical approval from the three clinical sites. Trial results will be disseminated through peer-reviewed publications and conference presentations. CONCLUSIONS: This trial makes a timely contribution to test a mobile application designed to improve the quality of life and delivery of care for patients with lung cancer. TRIAL REGISTRATION NUMBER: NCT03512015; Pre-results.

HTA programme response to the challenges of dealing with orphan medicinal products: Process evaluation in selected European countries.

BACKGROUND: Challenges commonly encountered in HTA of orphan medicinal products (OMPs) were identified in Advance-HTA. Since then, new initiatives have been developed to specifically address issues related to HTA of OMPs. OBJECTIVE AND METHODS: This study aimed to understand why these new HTA initiatives in England, Scotland and at European-level were established and whether they resolve the challenges of OMPs. The work of Advance-HTA was updated with a literature review and a conceptual framework of clinical, regulatory and economic challenges for OMPs was developed. The new HTA programmes were critiqued against the conceptual framework and outstanding challenges identified. RESULTS: The new programmes in England and Scotland recognise the challenges identified in demonstrating the value of ultra-OMPs (and OMPs) and that they require a different process to standard HTA approaches. Wider considerations of disease and treatment experiences from a multi-stakeholder standpoint are needed, combined with other measures to deal with uncertainty (e.g. managed entry agreements). While approaches to assessing this new view of value of OMPs, extending beyond cost/QALY frameworks, differ, their criteria are similar. These are complemented by a European initiative that fosters multi-stakeholder dialogue and consensus about value determinants throughout the life-cycle of an OMP. CONCLUSION: New HTA programmes specific to OMPs have been developed but questions remain about whether they sufficiently capture value and manage uncertainty in clinical practice.

Dealing with Uncertainty and Accounting for Social Value Judgments in Assessments of Orphan Drugs: Evidence from Four European Countries.

OBJECTIVES: To better understand the reasons for differences in reimbursement decisions for orphan drugs in four European countries that were not readily apparent from health technology assessment (HTA) reports and operating procedures. METHODS: Semistructured interviews with representatives of HTA bodies in England, Scotland, Sweden, and France were conducted. An interview topic guide was developed on the basis of findings from a systematic comparison of HTA decisions for 10 orphan drugs. Qualitative thematic data analysis was applied to the interview transcripts using the framework approach. RESULTS: Eight representatives from the four HTA bodies were interviewed between March and June 2015. Evidentiary requirements and approaches to dealing with imperfect or incomplete evidence were explored, including trial design and duration, study population and subgroups, comparators, and end points. Interviewees agreed that decisions regarding orphan drugs are made in a context of lower quality evidence, and the threshold of acceptable uncertainty varied by country. Some countries imposed higher evidentiary standards for greater clinical claims, which may be more challenging for orphan diseases. The acceptability of surrogate end points was not consistent across countries nor were the validation requirements. The most common social value judgments identified related to innovation, disease severity, and unmet need. Differences were seen in the way these concepts were defined and accounted for across countries. CONCLUSIONS: Although agreement was seen in evidentiary requirements or preferences, there were subtle differences in the circumstances in which uncertain evidence may be considered acceptable, possibly explaining differences in HTA recommendations across countries.

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL).

Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP's is realised.

Why do health technology assessment coverage recommendations for the same drugs differ across settings? Applying a mixed methods framework to systematically compare orphan drug decisions in four European countries.

PURPOSE: Health technology assessment (HTA) coverage recommendations differ across countries for the same drugs. Unlike previous studies, this study adopts a mixed methods research design to investigate, in a systematic manner, these differences. METHODS: HTA recommendations for ten orphan drugs appraised in England (NICE), Scotland (SMC), Sweden (TLV) and France (HAS) (N = 35) were compared using a validated methodological framework that breaks down these complex decision processes into stages facilitating their understanding, analysis and comparison, namely: (1) the clinical/cost-effectiveness evidence, (2) its interpretation (e.g. part of the deliberative process) and (3) influence on the final decision. This allowed qualitative and quantitative identification of the criteria driving recommendations and highlighted cross-country differences. RESULTS: Six out of ten drugs received diverging HTA recommendations. Reasons for cross-country differences included heterogeneity in the evidence appraised, in the interpretation of the same evidence, and in the different ways of dealing with the same uncertainty. These may have been influenced by agency-specific evidentiary, risk and value preferences, or stakeholder input. "Other considerations" (e.g. severity, orphan status) and other decision modulators (e.g. patient access schemes, lower discount rates, restrictions, re-assessments) also rendered uncertainty and cost-effectiveness estimates more acceptable. The different HTA approaches (clinical versus cost-effectiveness) and ways identified of dealing with orphan drug particularities also had implications on the final decisions. CONCLUSIONS: This research contributes to better understanding the drivers of these complex decisions and why countries make different decisions. It also contributed to identifying those factors beyond the standard clinical and cost-effectiveness tools used in HTA, and their role in shaping these decisions.

SCIENTIFIC AND SOCIAL VALUE JUDGMENTS FOR ORPHAN DRUGS IN HEALTH TECHNOLOGY ASSESSMENT.

OBJECTIVES: We explore how broader aspects of a treatment's value and the impact of the condition on patients not captured by routine health technology assessment (HTA) methods using clinical and economic evidence, defined as "other considerations," may influence HTA processes in different settings. METHODS: Countries included were England, Scotland, Sweden, and France. Data sources were the publicly available reports on HTA recommendations. Ten drugs with European Medicines Agency orphan designation and appraised in England were selected. Qualitative thematic analysis was used to systematically identify and code all "other considerations" based on a previously developed methodological framework, which also coded whether it was provided by stakeholders, and how it influenced the decision. RESULTS: A classification framework of scientific and social value judgments was developed and used throughout the study. A total of 125 "other considerations" were identified and grouped into ten subcategories based on the information provided. Eighteen to 100 percent of these, depending on the agency, were put forward as one of the main reasons for the final decision potentially contributing to accepting a higher incremental cost-effectiveness ratio or uncertain evidence. Some of these were nonquantified or nonelicited and pertained to the assessor's judgment. A taxonomy of these value judgments was created to be used in future cases. Results also contributed to better defining the determinants of social value and improving accountability for reasonableness. CONCLUSIONS: The systematic identification of the scientific and social value judgments enables to better understanding the dimensions of value, which can be used to improve their transparency and consistent use across decisions and settings.

Developing an evidence-based methodological framework to systematically compare HTA coverage decisions: A mixed methods study.

Health Technology Assessment (HTA) often results in different coverage recommendations across countries for a same medicine despite similar methodological approaches. This paper develops and pilots a methodological framework that systematically identifies the reasons for these differences using an exploratory sequential mixed methods research design. The study countries were England, Scotland, Sweden and France. The methodological framework was built around three stages of the HTA process: (a) evidence, (b) its interpretation, and (c) its influence on the final recommendation; and was applied to two orphan medicinal products. The criteria accounted for at each stage were qualitatively analyzed through thematic analysis. Piloting the framework for two medicines, eight trials, 43 clinical endpoints and seven economic models were coded 155 times. Eighteen different uncertainties about this evidence were coded 28 times, 56% of which pertained to evidence commonly appraised and 44% to evidence considered by only some agencies. The poor agreement in interpreting this evidence (κ=0.183) was partly explained by stakeholder input (ns=48 times), or by agency-specific risk (nu=28 uncertainties) and value preferences (noc=62 "other considerations"), derived through correspondence analysis. Accounting for variability at each stage of the process can be achieved by codifying its existence and quantifying its impact through the application of this framework. The transferability of this framework to other disease areas, medicines and countries is ensured by its iterative and flexible nature, and detailed description.

Direct cost of pars plana vitrectomy for the treatment of macular hole, epiretinal membrane and vitreomacular traction: a bottom-up approach.

PURPOSE: The direct cost to the National Health Service (NHS) in England of pars plana vitrectomy (PPV) is unknown since a bottom-up costing exercise has not been undertaken. Healthcare resource group (HRG) costing relies on a top-down approach. We aimed to quantify the direct cost of intermediate complexity PPV. METHODS: Five NHS vitreoretinal units prospectively recorded all consumables, equipment and staff salaries during PPV undertaken for vitreomacular traction, epiretinal membrane and macular hole. Out-of-surgery costs between admission and discharge were estimated using a representative accounting method. RESULTS: The average patient time in theatre for 57 PPVs was 72 min. The average in-surgery cost for staff was £297, consumables £619, and equipment £82 (total £997). The average out-of-surgery costs were £260, including nursing and medical staff, other consumables, eye drops and hospitalisation. The total cost was therefore £1634, including 30 % overheads. This cost estimate was an under-estimate because it did not include out-of-theatre consumables or equipment. The average reimbursed HRG tariff was £1701. CONCLUSIONS: The cost of undertaking PPV of intermediate complexity is likely to be higher than the reimbursed tariff, except for hospitals with high throughput, where amortisation costs benefit from economies of scale. Although this research was set in England, the methodology may provide a useful template for other countries.

Social and economic costs and health-related quality of life in non-institutionalised patients with cystic fibrosis in the United Kingdom.

BACKGROUND: This study aimed to determine the societal economic burden and health-related quality of life (HRQOL) of cystic fibrosis (CF) patients in the UK. METHODS: A bottom-up cost-of-illness, cross-sectional, retrospective analysis of 74 patients was conducted aiming to estimate the economic impact of CF. Data on demographic characteristics, health resource utilisation, informal care, productivity losses and HRQOL were collected from questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) instrument. RESULTS: Using unit costs for 2012 we found that the average annual cost for a CF patient was €48,603, with direct health care costs amounting to €20,854 (42.9 % of total costs), direct non-health care costs being €21,528 (44.3 %) and indirect costs attributable to productivity losses being €6,222 (12.8 %). On average, the largest expenditures by far were accounted for by informal care (44.1 %), followed by medications (14.5 %), acute hospitalisations (13.9 %), early retirement (9.1 %) and outpatient and primary health care visits (7.9 %). Sharp differences existed depending on whether CF patients were in need of caregiver help (€76,271 versus €26,335). In adult CF patients, mean EQ-5D index scores were 0.64 (0.93 in the general population) and mean EQ-5D visual analogue scale scores were 62.23 (86.84 in the general population); among caregivers, these scores were 0.836 and 80.85, respectively. DISCUSSION: Our analysis highlights the importance of the economic and quality of life consequences of CF from a societal perspective. The results highlight that beyond conventional costs such as acute hospitalisations, medication and outpatient and primary care visits, indirect costs related to informal care and early retirement, have significant societal implications. Similarly, our analysis showed that the average EQ-5D index score of adult CF patients was significantly lower than in the general population, an indication that a methodological bias may exist in using the latter in economic analyses. CONCLUSION: CF poses a significant cost burden on UK society, with non-health care and indirect costs representing 57 % of total average costs, and HRQOL being considerably lower than in the general population.