Real-world evidence for coverage determination of treatments for rare diseases.

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Usage and impact of patient-reported outcomes in epilepsy.

BACKGROUND: The use of patient-reported outcomes (PRO) in clinical practice is gaining increasing attention. This study aimed to provide a critical assessment of the current state-of-the-art and beliefs about the use of PRO in the management of people with epilepsy across some European countries. METHODS: Structured interviews were conducted with European experts to collect insights about (I) the personal experience with PRO; (II) the value and impact of PRO in the decision-making process at the national level; and (III) the interest for and use of PRO by national health authorities. RESULTS: Nine neurologists (Austria, Belgium, Czechia, Denmark, France, Greece, Italy, Poland, and United Kingdom), three health economists (Portugal, Romania, and Sweden), and one epidemiologist (Slovakia) participated. They all stated that PRO are collected at their own countries in the context of clinical trials and/or specific projects. During everyday clinical practice, PRO are collected routinely/almost routinely in Austria and Sweden and only at the discretion of the treating physicians in Czechia, Denmark, France, Greece, and Portugal. There was complete consensus about the favorable impact that the PRO can have in terms of clinical outcomes, healthcare resources utilization, and general patient satisfaction. Only participants from Portugal and Sweden answered that the PRO are perceived as very important by the National Health Authorities of their respective countries. CONCLUSIONS: Differences exist in attitudes and perspectives about PRO in epilepsy across Europe. An active plan is warranted to harmonize the measurement of PRO and ensure they can be relevant to people with epilepsy and health services.

A cross-country comparison of health-related quality of life in the United States, Sweden, and Norway during the first year of the COVID-19 pandemic.

BACKGROUND: Limited studies have directly compared health-related quality of life (HRQoL) in different countries during the COVID-19 global pandemic. The objective of this study was to evaluate the HRQoL outcomes in the US, Sweden, and Norway during the first year under the pandemic. METHODS: In April 2020, during early phase of the pandemic, separately in the US, Sweden, and Norway, we surveyed 2,734, 1,003 and 1,020 respondents, then again in January 2021, we collected 2,252, 1,013 and 1,011 respondents. The survey was first developed in English and translated into Swedish and Norwegian. Selected variables were used for the current study. We collected respondents' HRQoL using the EQ-5D-5L. Respondents' background information included their sociodemographic data, medical history, and COVID-19 status. We reported the EQ-5D-5L utility, EQ-VAS, and the proportion of problems with each of the EQ-5D-5L health subdomains. Population quality-adjusted life year (QALY) changes based on EQ-5D-5L utility scores were also calculated. Outcomes were stratified by age. One-way ANOVA test was used to detect significant differences between countries and Student's t-tests were used to assess the differences between waves. RESULTS: Respectively for the US, Sweden, and Norway, mean EQ-5D-5L utilities were 0.822, 0.768, and 0.808 in April 2020 (p < 0.001); 0.823, 0.783, and 0.777 in January 2021 (p < 0.001); mean EQ-VAS scores were 0.746, 0.687, and 0.692 in April 2020 (p < 0.001), 0.764, 0.682, and 0.678 in January 2021 (p < 0.001). For both waves, EQ-5D-5L utilities and EQ-VAS scores in the US remained higher than both Sweden and Norway (p < 0.001). Norwegians reported considerably lowered HRQoL over time (p < 0.01). Self-reported problems with anxiety/depression were highest for the US and Sweden, while Norwegians reported most problems with pain/discomfort, followed by anxiety/depression. The population QALYs increased in the US and Sweden, but decreased in Norway. CONCLUSIONS: In the first year of the pandemic, a rebound in HRQoL was observed in the US, but not in Sweden or Norway. Mental health issues during the pandemic warrant a major public health concern across all 3 countries.

Clinical Impression of Severity Index for Parkinson's Disease and Its Association to Health-Related Quality of Life.

Background: Clinical Impression of Severity Index for Parkinson's Disease (CISI-PD) is a simple tool that can easily be used in clinical practice. Few studies have investigated the relationship between health-related quality of life and the CISI-PD. Objective: To analyze the association of CISI-PD scores with those of generic (EQ-5D-5L) and Parkinson's disease (PD) disease-specific (Parkinson's Disease Questionnaire-8 [PDQ-8]) health-related quality of life assessments. Methods: Persons with idiopathic PD in the Swedish Parkinson's Disease registry with simultaneous registrations of CISI-PD and EQ-5D-5L and/or PDQ-8 were included. Correlations with EQ-5D dimensions were analyzed. The relationships between the CISI-PD, EQ-5D-5L, and PDQ-8 were estimated by linear mixed models with random intercept. Results: In the Swedish Parkinson's Disease registry, 3511 registrations, among 2168 persons, fulfilled the inclusion criteria. The dimensions self-care, mobility, and usual activities correlated moderately with the CISI-PD (r s = 0.60, r s = 0.54, r s = 0.57). Weak correlations were found for anxiety/depression and pain/discomfort (r s = 0.39, r s = 0.29) (P values < 0.001). The fitted model included the CISI-PD, age, sex, and time since diagnosis. The CISI-PD had a statistically significant impact on the EQ-5D and PDQ-8 (P values < 0.001). Conclusions: The CISI-PD provides a moderate correlation with the EQ-5D and could possibly be useful as a basis for defining health states in future health economic models and serving as outcomes in managed entry agreements. Nonetheless, the limitation of capturing nonmotor symptoms of the disease remains a shortcoming of clinical instruments, including the CISI-PD.

Cost-effectiveness of specialised manual therapy versus orthopaedic care for musculoskeletal disorders: long-term follow-up and health economic model.

Background: Physiotherapy is usually the first line of treatment for musculoskeletal disorders. If pain persists, an appointment with an orthopaedic surgeon is indicated, but many disorders for which patients are placed on orthopaedic waiting lists cannot be treated in an orthopaedic clinic. Specialised manual therapy, although not mainstream, can be an effective alternative to orthopaedic care, although its cost-effectiveness beyond 12 months is unknown. Objectives: To perform an 8-year follow-up of the quality of life and costs of specialised manual therapy versus standard orthopaedic care for working-age patients with common nonsurgical musculoskeletal disorders referred to orthopaedic surgeons and to develop a health economic model. Design: Cost-effectiveness study using Markov modelling. Methods: The index group of a previously published pragmatic randomised controlled trial received a maximum of five treatment sessions of specialised manual therapy, while the control group received orthopaedic 'care as usual'. At 3, 6, 12 and 96 months, Health-Related Quality of Life and costs were measured with Short Form Health Survey 36, Short Form Health Survey 6D and Diagnostic Related Groups. An incremental cost-effectiveness ratio was calculated, a Markov model was developed and a sensitivity analysis was performed. Results: Overall, 95% (n = 75) of the participants completed the 8-year follow-up. Recovery rates during the first 3 months ('per protocol') in the index and control group were 69% and 58%, respectively. The index group had 0.159 more gains in quality-adjusted life years and cost 40,270 SEK (€4027) less per patient over 8 years. The sensitivity analysis results were consistent with the main results. Conclusion: Specialised manual therapy dominated standard care after 8 years. The results of this small but very first study are promising; therefore, further exploration within other health care professions, clinics and/or countries is required. Our study raises questions about the triaging of orthopaedic outpatients, cost-effectiveness and resource allocation. Registration: Not applicable per the information provided by ClinicalTrials.gov. Plain Language Summary: Specialised manual therapy is more cost-effective than 'care as usual' for working-age patients referred to an orthopaedist. This study provides an 8-year follow-up of the cost effects and quality of life of a previously published trial. Why was this study conducted? The standard care for musculoskeletal pain consists of exercises with a physiotherapist in primary care. If the pain persists, a referral to an orthopaedic clinic is often made. Many of these referrals are inappropriate because they concern pain from muscles and joints that do not benefit from surgery or the resources available in an orthopaedic clinic. There is a gap in competence and treatment between primary and specialised care that is costly, time- and resource-consuming and causes prolonged patient suffering. Although specialised manual therapy (MT) is effective, its use is not mainstream. Costs and effects after more than 12 months of treatment that may shorten waiting lists have never been evaluated. What did the researchers do? Quality of life and costs were compared in 75 patients with nonsurgical disorders referred to orthopaedic surgeons at 8 years after treatment with specialised MT or standard orthopaedic care. A health economics model for the probability of recovery was also developed and tested. What did the researchers find? Compared with the control group, the study participants treated with specialised MT had a better quality of life, required fewer health care interventions, underwent less surgery, incurred significantly lower costs and demonstrated an increased probability of recovery. What do these findings mean? It seems probable that using specialised MT for an old, well-known structural problem may yield better treatment effects at a significantly lower cost. Our study findings suggest that policy recommendations should focus on costs and effects rather than resource utilisation alone. The study is small and requires expansion using its economic health model.

Valuation of Treatments for Rare Diseases: A Systematic Literature Review of Societal Preference Studies.

INTRODUCTION: We sought to synthesize published empirical studies that elicited and characterized societal valuations of orphan drugs and the attributes that may drive different valuations for orphan drugs versus other treatments. METHODS: We conducted a systematic literature review (SLR) in MEDLINE and EMBASE databases up to November 2, 2020. Search terms covered societal preferences and attributes of orphan drugs (e.g., disease prevalence, severity, burden, unmet needs, and benefits). RESULTS: We identified 38 eligible publications: 33 societal preference studies and 5 reviews discussing societal valuations and attributes of orphan drugs. Most publications suggested that a majority of respondents favored allocating funds to more prevalent diseases. However, trade-off studies and discrete-choice experiments found that survey participants chose to allocate resources to orphan drugs even when the cost per unit of health benefit was greater than for therapies for more prevalent diseases. Overall, 19 of 27 studies assessing severity in treatment valuation revealed that respondents prioritized patients with severe diseases over those with milder ones for equal health benefits. Members of the general public tended to prefer treatments for diseases with no alternative or when existing alternatives had limited efficacy over diseases with clear therapeutic alternatives. There was evidence that individuals preferred sharing resources, so no patient was left without treatment. CONCLUSIONS: Our SLR indicates the general public typically attaches greater value to orphan drugs than to other treatments for common diseases. This is not because of rarity per se, but primarily because of disease severity and lack of therapeutic alternatives typically associated with rare diseases.

Orphan drugs are drugs serving a substantial public health need by treating life-threatening or chronically debilitating medical conditions affecting a small number of people with very high unmet needs. We reviewed 38 published studies looking at drug characteristics that may cause people to value orphan drugs differently versus treatments for common conditions. Most people surveyed in these publications favored health care funds going to more prevalent diseases. However, some people preferred funding orphan drugs even when the cost versus health benefit was higher compared with treatments for more common diseases. The majority of studies that investigated the impact of disease severity on the valuation of treatments found that people prioritized patients with severe disease over those with milder disease, for the same extent of health benefit. People also preferred funding treatments for diseases that have no alternative treatments, or treatments with limited benefits, over treatments for diseases with many treatments or more effective treatments. We also found evidence of a societal preference for shared resources, meaning that no patient would be left without treatment, including those who receive limited benefits from health care resources, even if this does not lead to the maximization of health benefits across society. In conclusion, our literature review indicated that the general public attaches greater value to orphan drugs versus treatments for more common diseases, not because of rarity per se, but largely because the rare diseases treated by orphan drugs are often severe and have no or few treatment options.

Acceptance and application of a broad population health perspective when evaluating vaccine.

The traditional health economic analysis is limited to estimating the impact on the treated patient. As vaccines are usually aimed at preventing infectious diseases, they may be associated with additional values for the non-treated wider population. Although there are valid reasons for treating vaccines differently, and a wide support for a broader perspective in the literature (i.e., beyond the net costs and health gain related to the outcome for the vaccinated individual), it remains unclear to what extent the Health Technology Assessment (HTA) agencies accept and apply a broader perspective. The purpose of this study is to examine and discuss what type of consequences are relevant for a health economic analysis of vaccines and which consequences are considered by HTA agencies. The study includes a strategic review of literature and HTA decisions in Sweden and other countries, online round-table discussions with stakeholders in Sweden, and a basic estimation of the value of a COVID-19 vaccination in Sweden. The study shows that, other than herd effect, broader economic consequences for the population are generally not included in the economic evaluation of vaccines. Also, all economic consequences for the treated patient (production loss) and caregiver (health loss) are not always considered. The perspective chosen can have a major impact on the outcome of the analysis. A vaccine for COVID-19 is estimated to provide a value of €744-€956 per dose when using a societal perspective including broader consequences for the population. Providing a complete and appropriate picture of the value of vaccination is of importance to allocate resources efficiently, to provide incentives for vaccine development, and to show the cost of delaying decisions to implement a new vaccine.

Manual therapy versus advice to stay active for nonspecific back and/or neck pain: a cost-effectiveness analysis.

BACKGROUND: Low back and neck pain are the most common musculoskeletal disorders worldwide, and imply suffering and substantial societal costs, hence effective interventions are crucial. The aim of this study was to evaluate the cost-effectiveness of manual therapy compared with advice to stay active for working age persons with nonspecific back and/or neck pain. METHODS: The two interventions were: a maximum of 6 manual therapy sessions within 6 weeks, including spinal manipulation/mobilization, massage and stretching, performed by a naprapath (index group), respectively information from a physician on the importance to stay active and on how to cope with pain, according to evidence-based advice, at 2 occasions within 3 weeks (control group). A cost-effectiveness analysis with a societal perspective was performed alongside a randomized controlled trial including 409 persons followed for one year, in 2005. The outcomes were health-related Quality of Life (QoL) encoded from the SF-36 and pain intensity. Direct and indirect costs were calculated based on intervention and medication costs and sickness absence data. An incremental cost per health related QoL was calculated, and sensitivity analyses were performed. RESULTS: The difference in QoL gains was 0.007 (95% CI - 0.010 to 0.023) and the mean improvement in pain intensity was 0.6 (95% CI 0.068-1.065) in favor of manual therapy after one year. Concerning the QoL outcome, the differences in mean cost per person was estimated at - 437 EUR (95% CI - 1302 to 371) and for the pain outcome the difference was - 635 EUR (95% CI - 1587 to 246) in favor of manual therapy. The results indicate that manual therapy achieves better outcomes at lower costs compared with advice to stay active. The sensitivity analyses were consistent with the main results. CONCLUSIONS: Our results indicate that manual therapy for nonspecific back and/or neck pain is slightly less costly and more beneficial than advice to stay active for this sample of working age persons. Since manual therapy treatment is at least as cost-effective as evidence-based advice from a physician, it may be recommended for neck and low back pain. Further health economic studies that may confirm those findings are warranted. Trial registration Current Controlled Trials ISRCTN56954776. Retrospectively registered 12 September 2006, http://www.isrctn.com/ISRCTN56954776 .

The impact on quality of life of diet restrictions and disease symptoms associated with phenylketonuria: a time trade-off and discrete choice experiment study.

Phenylketonuria (PKU) is a metabolic disorder leading to a deficiency in the metabolism of phenylalanine (Phe). Elevated Phe levels in the blood, tissue and brain may lead to emotional, cognitive, and physical symptoms in adults. To control blood Phe levels, most individuals with PKU need to follow a strict, life-long Phe-restricted diet. The main objective of this study was to estimate the impact of PKU-related disease symptoms and dietary restrictions on health-related quality of life (HRQoL). This study was designed as a web-based survey using the methods of Time Trade-Off (TTO) and Discrete Choice Experiment with duration (DCETTO) in a survey of the Swedish general population and population with PKU. Data were collected using questionnaires for TTO diet (n = 509), TTO symptoms (n = 507), and DCETTO (n = 1117). The disutility of diet restrictions ranged from 0.050 for a partially restricted diet without medical food to 0.193 for a fully restricted diet with medical food in the TTO (DCE: 0.043-0.108). The disutility of experiencing symptoms (emotional, cognitive and physical) ranged from 0.148 for mild symptoms to 0.593 for severe symptoms in the TTO (DCE: 0.122-1.522). The study shows that both diet and symptoms have a significant negative impact on HRQoL in PKU and that utility estimates are largely consistent across methods and samples.

Variation in market access decisions for cell and gene therapies across the United States, Canada, and Europe.

Transformative cell and gene therapies have now launched worldwide, and many potentially curative cell and gene therapies are in development, offering the prospect of significant health gains for patients. Access to these therapies depend on decisions made by health technology assessment (HTA) and payer organizations. We sought to describe the emerging cell and gene therapies market access landscape by analyzing 17 US commercial payer medical policies, and HTA reports from five European countries and Canada. We found that some US health plans applied coverage restrictions more often than others (four plans applied restrictions in all decisions, while four plans applied restrictions in <30% of decisions). The European and Canadian HTA bodies recommend access to fewer therapies than US health plans, reflecting a more stringent approach in the context of limited evidence and high scientific uncertainty that is commonly associated with these treatments. Our findings suggest that patient access to approved cell and gene therapies is restricted in all regions studied, though the nature of these restrictions differs between US health plans and the European/Canada HTA recommendations. Payers, HTA groups, pharmaceutical companies, and other stakeholders should collaborate to more clearly define the "uncertainties" and develop market access policies that balance benefits of early access with ongoing data collection to close evidence gaps over time.