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Context: Recent debates and events have brought into question the effectiveness of existing regulatory frameworks for medical devices in the United States and Europe to ensure their performance, safety, and quality. This article provides a comparative analysis of medical device regulation in the two jurisdictions, explores current reforms to improve the existing systems, and discusses additional actions that should be considered to fully meet this aim. Medical device regulation must be improved to safeguard public health and ensure that high-quality and effective technologies reach patients. Methods: We explored and analyzed medical device regulatory systems in the United States and Europe in accordance with the available gray and peer-reviewed literature and legislative documents. Findings: The two regulatory systems differ in their mandate and orientation, organization, pre- and postmarket evidence requirements, and transparency of process. Despite these differences, both jurisdictions face similar challenges for ensuring that only safe and effective devices reach the market, monitoring real-world use, and exchanging pertinent information on devices with key users such as clinicians and patients. To address these issues, reforms have recently been introduced or debated in the United States and Europe that are principally focused on strengthening regulatory processes, enhancing postmarket regulation through more robust surveillance systems, and improving the traceability and monitoring of devices. Some changes in premarket requirements for devices are being considered. Conclusions: Although the current reforms address some of the outstanding challenges in device regulation, additional steps are needed to improve existing policy. We examine a number of actions to be considered, such as requiring high-quality evidence of benefit for medium- and high-risk devices; moving toward greater centralization and coordination of regulatory approval in Europe; creating links between device identifier systems and existing data collection tools, such as electronic health records; and fostering increased and more effective use of registries to ensure safe postmarket use of new and existing devices.

How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find four spatially distinct stem cell populations at the top and bottom of rete ridges and transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling suggests that basal cell populations serve as crucial signaling hubs to maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest that transitional basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed transitional basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity. The mechanisms regulating stem cells to give rise to human interfollicular epidermis are unclear. Here, the authors use single cell RNA sequencing to identify heterogeneity within the human neonatal interfollicular epidermis and distinct spatial positioning of at least four basal stem cell populations.

Health economic evaluations are comparative analyses of alternative courses of action in terms of their costs and consequences. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, published in 2013, was created to ensure health economic evaluations are identifiable, interpretable, and useful for decision making. It was intended as guidance to help authors report accurately which health interventions were being compared and in what context, how the evaluation was undertaken, what the findings were, and other details that may aid readers and reviewers in interpretation and use of the study. The new CHEERS 2022 statement replaces previous CHEERS reporting guidance. It reflects the need for guidance that can be more easily applied to all types of health economic evaluation, new methods and developments in the field, as well as the increased role of stakeholder involvement including patients and the public. It is also broadly applicable to any form of intervention intended to improve the health of individuals or the population, whether simple or complex, and without regard to context (such as health care, public health, education, social care, etc). This summary article presents the new CHEERS 2022 28-item checklist and recommendations for each item. The CHEERS 2022 statement is primarily intended for researchers reporting economic evaluations for peer reviewed journals as well as the peer reviewers and editors assessing them for publication. However, we anticipate familiarity with reporting requirements will be useful for analysts when planning studies. It may also be useful for health technology assessment bodies seeking guidance on reporting, as there is an increasing emphasis on transparency in decision making.

Health economic evaluations are comparative analyses of alternative courses of action in terms of their costs and consequences. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, published in 2013, was created to ensure health economic evaluations are identifiable, interpretable, and useful for decision making. It was intended as guidance to help authors report accurately which health interventions were being compared and in what context, how the evaluation was undertaken, what the findings were, and other details that may aid readers and reviewers in interpretation and use of the study. The new CHEERS 2022 statement replaces previous CHEERS reporting guidance. It reflects the need for guidance that can be more easily applied to all types of health economic evaluation, new methods and developments in the field, as well as the increased role of stakeholder involvement including patients and the public. It is also broadly applicable to any form of intervention intended to improve the health of individuals or the population, whether simple or complex, and without regard to context (such as health care, public health, education, social care, etc). This summary article presents the new CHEERS 2022 28-item checklist and recommendations for each item. The CHEERS 2022 statement is primarily intended for researchers reporting economic evaluations for peer reviewed journals as well as the peer reviewers and editors assessing them for publication. However, we anticipate familiarity with reporting requirements will be useful for analysts when planning studies. It may also be useful for health technology assessment bodies seeking guidance on reporting, as there is an increasing emphasis on transparency in decision making.

BackgroundRare 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.ObjectivesThis 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.MethodsAll 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.ResultsWe 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%).ConclusionsThe 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.

Background This paper addresses the question of what a reasonable price for an orphan drug is. The research proposes a way to adjust an established payer/HTA body incremental cost-effectiveness threshold (CET) to take account of differences in patient populations and costs of research and development in order to sustain prices that generate rates of return from investments in developing orphan drugs that are no greater than the industry average. Methods We investigated the cost of conducting research for orphan drugs as compared to non-orphan drugs, as well as patient population sizes targeted by orphans and non-orphans. We provided an empirical illustration based on novel drug approvals of orphan and non-orphan drugs of the FDA between 2011 and 2015 (N = 182). Results Using, for illustration, the NICE incremental CET (£20 K per QALY) as an anchor and adjusting by R&D costs and expected market revenue, we estimated the adjusted reasonable CET for orphan drugs to be £39.1 K per QALY at the orphan population cut-off and £78.3 K per QALY at the orphan population mid-point. For ultra-orphan drugs the adjusted CET was £937.1 K. Conclusions We propose one general method for establishing a reasonable price for an orphan drug, based on the proposition that rates of return for investments in developing orphan drugs should not be greater than the industry average. More research is required on data and assumptions, but with the data and assumptions we use, we find that in order to secure such a reasonable price for an orphan drug, the CET for orphans would need to be higher. This could be one approach for establishing the maximum allowable price society should be willing to pay, although decision-makers may still wish to negotiate a lower price, or refuse to pay such a premium over the value-based price in order to treat these groups of patients.

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.

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.