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.

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.

'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.

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.

PARS PLANA VITRECTOMY FOR DIABETIC MACULAR EDEMA: A Systematic Review, Meta-Analysis, and Synthesis of Safety Literature.

PURPOSE: To assess the risk and benefit of pars plana vitrectomy for diabetic macular edema. METHODS: The authors conducted a systematic literature review using PubMed, EMBASE, Web of Science, and Cochrane Central Database of Controlled Trials until September 2014. The population was patients with diabetic macular edema, intervention vitrectomy, comparator macular laser or observation, and efficacy outcome visual acuity and central retinal thickness. Safety outcomes were intraoperative and postoperative surgical complications. The efficacy meta-analysis included only randomized controlled trials. The safety analysis included prospective, retrospective, controlled, and uncontrolled studies. RESULTS: Five studies were eligible for the efficacy meta-analysis (n = 127 eyes) and 40 for the safety analysis (n = 1,562 eyes). Combining follow-up intervals from 6 to 12 months, the meta-analysis found a nonsignificant 2 letter visual acuity difference favoring vitrectomy, and a significant 102 µm greater reduction in central retinal thickness favoring vitrectomy, but a post hoc subgroup analysis found that a 6-month central retinal thickness benefit reversed by 12 months. The most frequent complications were retinal break (7.1%), elevated intraocular pressure (5.2%), epiretinal membrane (3.3%), and vitreous hemorrhage (2.4%). Cataract developed in 68.6% of 121 phakic eyes. CONCLUSION: Vitrectomy produces structural and functional improvements in select eyes with diabetic macular edema, but the visual gains are not significantly better than with laser or observation. No major safety concerns were identified.

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.

Pars plana vitrectomy for vitreomacular traction syndrome: a systematic review and metaanalysis of safety and efficacy.

PURPOSE: To determine the safety and efficacy of pars plana vitrectomy for vitreomacular traction. METHODS: Articles reporting visual acuity change before and after pars plana vitrectomy were selected using a systematic literature review with predefined eligibility criteria. Visual acuities were converted to logarithm of the minimum angle of resolution (logMAR), weighted for study size, and pooled across studies. Safety outcomes were also pooled across studies. RESULTS: Twenty-one of 460 articles were eligible. Mean (±standard deviation) logMAR visual acuity improved from 0.67 ± 0.55 to 0.42 ± 0.45 (n = 259 eyes) after pars plana vitrectomy (from 20/94 to 20/53 Snellen). In series of at least 20 eyes, mean visual acuity improved in all 5 studies (sign test, P = 0.0625). Of 392 eyes, 9.2% lost visual acuity, 11.7% were unchanged, and 64.3% improved; 32.9% of 217 eyes gained ≥2 Snellen lines. The most common postoperative complications were cataract (34.7% of 304 eyes; 63.2% of 68 phakic eyes), epiretinal membrane (5.7% of 348 eyes), and retinal detachment (4.6% of 348 eyes). Cataract surgery was undertaken in 10.5% of eyes. CONCLUSION: The visual acuity gains after pars plana vitrectomy for vitreomacular traction are relatively modest, but visual acuity change may not fully reflect symptomatic relief.

Symptomatic vitreomacular adhesion.

BACKGROUND: Symptomatic vitreomacular adhesion describes symptomatic loss of visual function as a result of vitreous traction at the macula. METHODS: Literature review. RESULTS: Symptomatic vitreomacular adhesion can occur in isolation as vitreomacular traction, which may lead to the development of a macular hole, or it may occur alongside epiretinal membrane. It is likely to be associated with age-related macular degeneration and possibly diabetic maculopathy, although this is less certain. The treatment depends largely on the cause, but options include observation, vitrectomy, and pharmacologic vitreolysis. Small uncontrolled trials have also explored the use of an intravitreal gas bubble as a means of releasing VMA. If all cases of sVMA are considered together, then the burden of illness is substantial, with a prevalence of ∼0.35 per 100 population (excluding epiretinal membrane). Furthermore, there may be many more cases of undiagnosed sVMA. CONCLUSION: The recent introduction of ocriplasmin is likely to increase interest in sVMA. Clinical trials suggest that it has a role in the treatment of vitreomacular traction and Stages 1 to 3 macular holes but not primarily as a treatment of epiretinal membrane. Its role in other diseases associated with VMA remains to be determined.

Vitreous attachment in age-related macular degeneration, diabetic macular edema, and retinal vein occlusion: a systematic review and metaanalysis.

PURPOSE: To determine if there is an association of vitreous attachment and wet age-related macular degeneration (AMD), diabetic macular edema, and retinal vein occlusion. METHODS: Systematic review and metaanalysis. RESULTS: Sixteen of 1,025 articles were eligible. In wet AMD, the prevalence of vitreomacular adhesion and posterior vitreous detachment was 23% (654 eyes) and 41% (251), respectively. Vitreomacular adhesion prevalence was 2.15 times that of controls (95% confidence interval, 1.34-3.48; p = 0.002) and 2.54 times that of dry AMD (confidence interval, 0.88-7.36; p 0.09); posterior vitreous detachment prevalence was lower than controls (relative risk 0.77; confidence interval, 0.64-0.93; p = 0.007) and dry AMD (0.56; confidence interval, 0.27-1.14; p = 0.11). It was not possible to determine the prevalence of vitreous attachment in diabetic macular edema, but vitreomacular traction was present in 29% of 188 surgical cases. The prevalence of posterior vitreous detachment in eyes with central and branch retinal vein occlusion was 30% (56 eyes) and 31% (71 eyes), respectively, versus 25% (64 eyes) in controls. CONCLUSION: Observational studies of sufficient quality indicate that eyes with wet AMD have double the expected prevalence of vitreomacular adhesion and are less likely to have a posterior vitreous detachment. More controlled studies of diabetic macular edema and retinal vein occlusion are needed.

Commonalities and differences in HTA outcomes: a comparative analysis of five countries and implications for coverage decisions.

OBJECTIVE: To identify diverging HTA recommendations across five countries, understand the rationale for decision-making in specific therapeutic categories, and suggest ways forward to minimize these inter-country differences. METHODS: A comparative analysis of HTA recommendations for 287 drug-indication pairs appraised by five countries (England, Scotland, Sweden, Canada, and Australia) between 2007 and 2009, including an in-depth analysis of two case studies. Agreement levels were measured using kappa scores. Associations were explored through correspondence analysis. RESULTS: Significant inter-country variability in the HTA recommendations exists: 46% of the drug-indication pairs studied received diverging recommendations across countries. The level of agreement between agencies was poor to moderate. Associations between HTA recommendations issued by each HTA body per therapy area (cancer, orphan, CNS) differed from the general pattern observed across the complete sample. Expectations from HTA bodies in terms of relative effectiveness differ depending on the drug and disease's characteristics, although agency-specific guidelines are homogeneous for all treatments. POLICY IMPLICATIONS: Distinguishing and accounting for the specifics underpinning individual conditions and their characteristics in HTA processes may constitute a way forward to improved HTA methods, while increasing transparency in the expectations that HTA bodies have in terms of relative effectiveness of the drug depending on these characteristics.