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

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

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

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

Molecular Targets of Omega 3 and Conjugated Linoleic Fatty Acids – “Micromanaging” Cellular Response

Essential fatty acids cannot be synthesized de novo by mammals and need to be ingested either with the diet or through the use of supplements/functional foods to ameliorate cardiovascular prognosis. This review focus on the molecular targets of omega 3 fatty acids and conjugated linoleic acid, as paradigmatic molecules that can be exploited both as nutrients and as pharmacological agents, especially as related to cardioprotection. In addition, we indicate novel molecular targets, namely microRNAs that might contribute to the observed biological activities of such essential fatty acids

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 infuenced 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 signifcant 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 evidenc

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 (DME). Methods. We 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 DME, intervention vitrectomy, comparator macular laser or observation, and efficacy outcome visual acuity and central retinal thickness (CRT). Safety outcomes were intra- 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 non-significant 2 letter visual acuity difference favoring vitrectomy, and a significant 102 micron greater reduction in CRT favoring vitrectomy, but a post-hoc subgroup analysis found that a 6 month CRT 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. Conclusions. Vitrectomy produces structural and functional improvements in select eyes with DME, but the visual gains are not significantly better than with laser or observation. No major safety concerns were identified

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

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 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 US 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

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

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

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. 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. 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. 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