Before a high-risk medical device is approved for implantation into patients, there should be evidence not only of its performance and safety with a favourable benefit-risk ratio, but also of its clinical efficacy. Regulatory guidance on study methodologies is lacking, however, so the European Commission funded the CORE-MD project (Coordinating Research and Evidence for Medical Devices) to advise regulators on appropriate designs for clinical trials of high-risk devices. The CORE-MD consortium recommends that evaluation should be planned in four stages. Randomised controlled trials should be performed more often, against active comparators reflecting the best available treatment, or using sham interventions with ethical safeguards. Large trials can be managed efficiently using an electronic database or registry. Non-randomised clinical studies can apply objective performance criteria or other validated patient-relevant outcome measures, with adjustments to minimise bias. Full transparency of results from clinical investigations is essential. Proportionate regulation of breakthrough or orphan devices for independently-defined serious unmet needs may involve approval with less evidence, but on condition of subsequent confirmatory studies. These CORE-MD consensus proposals have been submitted to European Union medical device regulators, to be considered as a basis for more transparent and predictable requirements for clinical evidence. Funding:The CORE-MD project was funded as a Coordination and Support action from the European UnionHorizon 2020 research and innovation programme, under grant agreement 965246.

Objectives The EUnetHTA Core Model (R) is well-established in the HTA community. Some recommendations of corresponding guidance documents leave room for alternative methodological choices. Considering the new HTA regulation (HTAR), we aimed to identify needs for concretization (NCs) in EUnetHTA guidance and provide indicative methodological options.Methods We carried out a qualitative document analysis and structured group discussion. Twenty-two EUnetHTA documents were screened using transparent criteria. Identified NCs were classified into topics according to the PRISMA statement and presented to Austrian HTA practitioners (n = 11) during a structured group discussion. Participants rated NC's importance. To identify potential solutions, selected key handbooks for generic (Cochrane) and HTA-specific (IQWIG/NICE) evidence synthesis were systematically reviewed and matching content was charted against the NCs.Results Thirty-two topics with varying numbers of NCs were identified, twenty-six during the screening process, and six from the group discussion. Most of the topics related to evidence synthesis methods (nine topics), evidence eligibility criteria (nine topics), risk of bias (three topics), and certainty assessment (three topics). Other topics related to information sources, search strategy, data collection process, data items, effect measures, and reporting bias. One or more methodological approaches and recommendations could be identified for each identified topic from the included methodological handbooks.Conclusions Our analysis identified a need for concretization in some EUnetHTA guidelines. The structured overview of methodological options may support HTA doers in adapting and applying the guidelines to the national and local practical context.

The objectives were to summarise the evidence and clinical experts' views comparing the use of decentralised produced chimeric antigen receptor (CAR) T-cell therapies versus commercially available products, regarding drug costs, time to finalised product and other reported advantages, disadvantages, challenges and facilitators. A literature review according to the PRISMA guidelines was conducted in Medline, Embase and Trip databases. Publications were included if they reported information on cost estimates, time to finalised products and other outcomes of interest of a decentralised CAR T-cell production strategy. A structured interview guide was developed and used for qualitative expert interviews. Five experts were purposively selected, and interviews were either conducted face-to-face or online, and recorded for the purpose of transcription. Transcripts were analysed and categories and codes extracted. Reporting is based on the COREQ checklist for reporting qualitative research. Costs of decentralised produced CAR T-cells appear to be lower by a factor two to 14, compared with commercial products. But there is high uncertainty about this estimate, because it is unclear whether cost components included are comparable and due to the heterogeneity of the studies. The most commonly reported advantages were proximity to patients and decreased product risks and costs, whereas the continuing dependency on centrally manufactured reagents and specific characteristics of 'fresh' CAR T-cells are reported as disadvantages. Compliance with regulatory requirements is mentioned as the biggest challenge. The availability of closed-system production devices is reported as one main facilitator, as are clear commitment, secured financing and knowledge transfer from already experienced centres. Apparent cost differences open a field for healthcare decision-makers to discuss and justify investment costs for implementation of a complementing decentralised production programme and to realise other associated benefits of such a strategy, such as flexibility, patient proximity and expanding patient access.

Background In surgical advancements, robot-assisted surgery (RAS) holds several promises like shorter hospital stays, reduced complications, and improved technical capabilities over standard care. Despite extensive evidence, the actual patient benefits of RAS remain unclear. Thus, our systematic review aimed to assess the effectiveness and safety of RAS in visceral and thoracic surgery compared to laparoscopic or open surgery. Methods We performed a systematic literature search in two databases (Medline via Ovid and The Cochrane Library) in April 2023. The search was restricted to 14 predefined thoracic and visceral procedures and randomized controlled trials (RCTs). Synthesis of data on critical outcomes followed the Grading of Recommendations, Assessment, Development, and Evaluation methodology, and the risk of bias was evaluated using the Cochrane Collaboration’s Tool Version 1. Results For five out of 14 procedures, no evidence could be identified. A total of 20 RCTs and five follow-up publications met the inclusion criteria. Overall, most studies had either not reported or measured patient-relevant endpoints. The majority of outcomes showed comparable results between study groups. However, RAS demonstrated potential advantages in specific endpoints (e.g., blood loss), yet these findings relied on a limited number of low-quality studies. Statistically significant RAS benefits were also noted in some outcomes for certain indications—recurrence, quality of life, transfusions, and hospitalisation. Safety outcomes were improved for patients undergoing robot-assisted gastrectomy, as well as rectal and liver resection. Regarding operation time, results were contradicting. Conclusion In summary, conclusive assertions on RAS superiority are impeded by inconsistent and insufficient low-quality evidence across various outcomes and procedures. While RAS may offer potential advantages in some surgical areas, healthcare decisions should also take into account the limited quality of evidence, financial implications, and environmental factors. Furthermore, considerations should extend to the ergonomic aspects for maintaining a healthy surgical environment. Graphical abstract

Background For most digital health applications (DiGA) only limited evidence of benefit is available. Currently available assessment frameworks do not cover all domains of a full health technology assessment (HTA). Additionally, technology-specific aspects are required for the evaluation of DiGA. This work aimed to analyze the available assessment frameworks and design an evaluation process for DiGA. Methods By a systematic literature search six assessment frameworks for DiGA were selected and analyzed. A hand search for strategies on DiGA of selected countries was conducted. Results Of the analyzed assessment frameworks four described study designs. One assessment framework proposed a risk classification of DiGA. Aspects of artificial intelligence were assessed by one assessment framework. The analyzed countries have differing strategies for reimbursement of DiGA. Conclusion Assessment frameworks for DiGA are very heterogeneous. There are efforts to find regulations for DiGA on a national level. When evaluating DiGA, a staged approach considering risk classes with subsequent evaluation of relevant HTA aspects is recommended.

OBJECTIVE:This systematic review provides an update on outcomes for patients with spinal muscular atrophy (SMA) type 1 to 4 treated with approved therapeutics, including the most recent, risdiplam, for an observation period of up to 48 months. METHODS:A systematic literature search was conducted in July 2023 in four databases. Selected publications were assessed for internal validity and risk of bias by two authors and relevant data were extracted into standardised tables. Results were summarised narratively as substantial heterogeneity of studies prevents meaningful quantitative analysis. RESULTS:Twenty observational studies and one RCT were included in the analysis, fifteen studies on nusinersen, one on onasemnogene abeparvovec and two on risdiplam. Evidence supports the effectiveness of the therapies in motor function improvement for up to 48 months of follow-up in the SMA types specified in their respective indications. Better results were observed with earlier treatment initiation and higher baseline function. Whilst motor improvement was consistently observed, regardless of SMA type or treatment used, we noted no significant improvements in respiratory and nutritional outcomes. Quality of life endpoints were rarely investigated. Adverse events were common but seldom classified as treatment-related except for post-lumbar puncture syndrome, which was frequently reported across nusinersen studies. CONCLUSION:The treatment of SMA with the new therapies changes the disease phenotype with changes in motor function far exceeding any improvement in respiratory and nutritional function. Questions persist on long-term efficacy, potential regressions, impact on quality of life and social functioning, therapy duration, and discontinuation indicators.

IntroductionCosts for pharmaceutical products are increasing. Pharmaceutical companies claim that high research and development (R&D) costs are the reason for the steep price increase of new products. However, there exists little data to support such claims; there is a lack of transparency in R&D cost reporting. This research intends to analyze and to disaggregate the costs of pharmaceutical R&D.MethodsStudies on the costs of introducing new medications to the market can differ substantially in their methodology, their origin of data, and their results. A scoping review was conducted on costs of R&D for pharmaceutical products using Embase, PubMed, and EconLit, using a combination of the terms “drug research and development” and “costs” or “drug research and development” and “expenditure.” Additionally, semi structured interviews with 16 experts from non-governmental organizations (NGOs), pharmaceutical companies, academic researchers, and not-for-profit pharmaceutical companies were conducted to identify the main driving factors for rising costs of new drugs.ResultsOut of 24 studies that analyzed mixed therapeutic fields, the five highest cost estimates had affiliations with industry or received funding from pharmaceutical companies. Non-affiliated researchers are unable to reproduce studies that use confidential data and therefore cannot check the validity of the results. Additionally, different definitions for R&D make analyzing costs challenging. The interviewees emphasized that driving factors influencing costs for pharmaceutical R&D are therapeutic indication, drug complexity, number of patients in clinical trials, length of the development process, and attrition rates.ConclusionsDue to the diverse nature of drug development and the confidential information held by pharmaceutical companies, it is a challenge to provide an exact assessment of the average costs of pharmaceutical R&D. Transparency policies with well-defined definitions for R&D are necessary to level the information asymmetries between the private and the public at price negotiations.

In many countries, the economics domain forms a routine part of health technology assessments (HTA) next to analyzing the comparative effectiveness and safety of a technology. The method applied most often is economic evaluation, such as cost-effectiveness analysis, which is supposed to support the efficient use of resources. In Austria, economic evaluation has played a negligible role in HTA and reimbursement decisions, even though the country faces the same public healthcare sustainability challenges as others. In this commentary, we argue that while health economics will need to play a more active role in HTA-related decision support to deal with those challenges, current approaches in other countries may have to be broadened to fit the Austrian context. We are outlining four arguments to underpin this perspective: First, economic evaluations (in their current form) are of limited benefit for supporting reimbursement decisions of new high-priced technologies. Second, a broader variety of health economic methods is needed to address the scope of technologies. Third, applying health economic methods requires a reflection on their underlying values. Finally, health economics within HTA needs to go beyond microeconomic analysis of interventions. We are suggesting several alternative methods and approaches, encouraging out-of-the-box thinking and experimenting with methods developed in the academic context but rarely applied in routine HTA. Although some of our topics are unique to Austria, others may equally apply to other healthcare systems. With our thoughts, we aim to stimulate discussions for further developing health economics within HTA in Austria and internationally.

Objectives: To synthesise the available evidence of wearable cardioverter defibrillator (WCD) therapy as an add-on measure to optimal medical therapy (OMT) or as a replacement of hospital stay. Methods: An update systematic review (SR) of comparative effectiveness and safety of WCD therapy was con-ducted. We included randomised controlled trials (RCT), prospective comparative studies and prospective un-controlled studies with at least 100 patients. A narrative synthesis of the evidence was conducted.Results: One RCT (n = 2348) and further eleven observational studies (n = 5345) fulfilled our inclusion criteria. In the only available RCT, the use of the WCD was not statistically associated with a clinical benefit on arrhythmic mortality in post-myocardial infarction (MI) patients with an ejection fraction of <= 35%. The compliance with WCD therapy was low in the RCT and high in observational studies, with ten observational studies reporting on a daily wear time between 20 and 23.5 h. The range of percentage of patients receiving at least one appropriate shock was 1-4.8% and the rate of first shock success was reported to be 100% in three studies. Serious adverse events (SAEs) such as inappropriate shocks occurred rarely, with between 0% and 2% of patients being inap-propriately shocked within ten observational studies. In one of the observational studies, two patients (2%) were allergic to nickel developing skin rash and false alarms occurred in 58 patients (57%) in this study. Another registry study (n = 448) reported milder AEs, such as dermatitis and pressure marks, occurring in 0.9% and 0.2% of enrolled patients, respectively. Conclusion: The only available RCT failed to show superiority of add-on use of WCD in post MI patients. Observational evidence shows that the compliance with WCD is good, but the evidence is afflicted with selection bias and the inclusion of diverse mixed patient populations diluting the ability to draw indication-specific conclusions on the utility of the device. More comparative data is needed to justify continuing or expanding use of WCD therapy.

Purpose: To elaborate a concept for implementing digital health applications (DiHA), including prioritisation criteria (PC) for the Austrian context and an overview of available prioritised DiHA. Methods: Based on European DiHA-listings and input by Austrian experts, a categorised meta-directory of DiHAs was created. PC were developed to reflect, inter alia, the provisions of the Austrian General Insurance Act, and were applied to the meta-directory to identify DiHAs potentially relevant for the Austrian statutory health in-surance. An iterative process with expert involvement was used to tailor an existing reimbursement framework to the Austrian setting. Results: The meta-directory comprised 132 DiHAs. Developed PC focused on plausibility (German language) and legal aspects (treatment/monitoring of chronic conditions), while other criteria (e.g. interoperability standards) were considered optional. After applying the PC, 38 DiHAs were potentially relevant in the Austrian setting. Of these, only seven supported current health record integration. Most of the prioritised DiHAs reported on CE marking (29/38) and data protection (35/38), while reporting on risk class (10/38) and technical algorithms (0/ 38) was sparse. For DiHA reimbursement, a four-step process is proposed: identification (ideally based on needs assessment); filtering based on PC; review of technical, regulatory and evidentiary requirements; and health technology assessment.Conclusion: The proposed concept can offer guidance for policy makers (e.g., on prioritising available DiHAs) and may further foster scientific debate with regard to DiHA implementation. Further discussion on how to fully incorporate regulatory, technical, and evidentiary criteria is needed. Attention should be given to national implementation requirements, reassessment criteria, and appropriate remuneration schemes.

OBJECTIVES:This article presents the mapping of horizons scanning systems (HSS) for medical devices, conducted by the Medical Devices Working Group of the International Horizon Scanning Initiative (IHSI MDWG). It provides an overview of the identified HSS, highlights similarities and differences between the systems, and lessons learned. METHODS:Potentially relevant HSS were identified through literature searches, scan of an overview of EuroScan members, and input from the IHSI MDWG members. Structured information was collected from organizations that confirmed having an HSS for medical devices. RESULTS:Sixteen initiatives could be identified, of which 11 are currently ongoing. The purposes of the HSS range from raising awareness of trends and new developments to managing informed decisions on innovative health services in hospitals. The time-horizon is most often 3 years up to a few months before market entry. Three models of identification of new technologies crystallized: a reactive (stakeholders outside HSS inform), a pro-active (actively searching multifold sources), and a hybrid model. Prioritization is often conducted by separate committees via scoring or debate. The outputs focus either on in-depth information of single technologies or on a class of technologies or on technologies in specific disease areas. CONCLUSIONS:The identified HSS share the common experience that horizon scanning (HS) for medical devices is a resource-intensive exercise that requires a dedicated and skilled team. Insights into the identified HSS and their experiences will be used in the continued work of the IHSI MDWG on its proposal for an IHSI HSS for medical devices.

IntroductionThe purpose of this systematic review is to evaluate whether implantable versus injectable bulking agents (second-line therapies) are equal/superior in terms of effectiveness (severity, quality of life [QoL], sustainability) and safety (adverse events) for fecal incontinence (FI).MethodsA systematic review was conducted and five databases were searched (Medline via Ovid, Embase, Cochrane Library, University of York Centre for Reviews and Dissemination, and International Network of Agencies for Health Technology Assessment database). In-/exclusion criteria were predefined according to the PICOS scheme. The Institute of Health Economics risk of bias (RoB) tool assessed studies’ internal validity. According to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, the strength of evidence for safety outcomes was rated. A qualitative synthesis of the evidence was used to analyse the data.ResultsSix prospective uncontrolled trials (143 patients) were included. The evidence consists of six prospective single-arm, before-after studies fulfilling the inclusion criteria for assessing clinical effectiveness and safety for implantable bulking agents. FI severity (Cleveland Clinic FI Score) statistically significantly improved to three months (p<0.01) and six months (p<0.05) follow-up (five studies). Improvements in severity sustainability were reported after 12, 14 (p<0.01), and 36 (p<0.0001) months postoperatively. Improved disease-related QoL (FI QoL Score) was found (p<0.05) 12 months after surgery, and statistically significant improvements in QoL’s sustainability after 12 months (one study).Procedure-related adverse events (n=3) occurred, where prostheses extruded during surgery, and anal discomfort/pain was felt (n=11). Device-related adverse events, i.e., prostheses’ dislodgement (n=31) and removed/extruded prostheses (n=3), occurred. Studies were judged with moderate/high RoB. The strength of evidence for safety was judged to be very low.ConclusionsImplantable bulking agents might be an effective and safe minimally invasive option in FI treatment if conservative therapies fail. FI severity significantly improved, but not QoL, which needs to be explored in further studies. Due to the uncontrolled nature of the case series, comparative studies need to be awaited.

Objectives In spring 2020, The European network for Health Technology Assessment (EUnetHTA) decided to join forces to produce best evidence to inform health policy in the COVID-19 pandemic. The objective of this paper is to describe the process and output of the coordinated and collaborative activities of EUnetHTA. Methods Relevant published and internal documents were retrieved for a descriptive analysis of EUnetHTA processes, methods, and outputs related to EUnetHTA's response to the pandemic. Results Process: In April 2020, a COVID-19 task force was set up and a survey collected pressing health policy questions across Europe. Two coordinating agencies for diagnostic tests and therapeutics were assigned. A process for prioritization and selection was set up for therapeutics, as well as explicit starting and stopping rules. Methodology: To increase a timely response, it was agreed that the rapid collaborative reviews (rapid CRs) would not require the consultation of manufacturers and the involvement of external experts, but would not differ in the methods and conduct of the systematic search, review, and synthesis of all available evidence, nor in the requirement for reviewing by EUnetHTA partners. Final reports: The joint effort resulted in the production of two rapid CRs on diagnostic tests, nineteen collaborative rolling reviews on therapeutics, three of which later moved to rapid CRs. Conclusions During COVID-19 pandemic, the EUnetHTA partners proved capable of prompt collaboration, which allowed speeding up the production and release of high-quality EUnetHTA outputs, while the relationships with the other European institutions facilitated their quick dissemination.

IntroductionThis study aims to (i) describe the (evidence-based) reimbursement process of hospital individual services, (ii) evaluate the accordance between evidence-based recommendations and reimbursement decision of individual services and (iii) elaborate potential aspects that play a role in the decision-making process in Austria.MethodsThe reimbursement process is described based on selected relevant sources such as official documents. Evidence-based recommendations and subsequent reimbursement decisions for the annual maintenance of the hospital individual service catalogue in Austria between 2008 and 2020 were analyzed using a mixed methods approach, encompassing descriptive statistics and a focus group with Austrian decisionmakers.ResultsOne hundred and eighteen evidence-based recommendations were analyzed. There were 93 (78.8%) negative and 25 (21.2%) positive evidence-based recommendations. In total, 107 out of 118 evidence-based recommendations (90.1%) did not lead to a deviating reimbursement decision. We identified six aspects that may have played a role in the decision-making process for the annual maintenance of the hospital individual service catalogue, with clinical evidence being the most notable. Further aspects included quality assurance/organizational aspects (i.e., structural quality assurance), costs (if comparable to already existing medical services, not: cost-effectiveness), procedural aspects (e.g., if certain criteria for adoption have not been met formally through the proposals), “other countries” (i.e., taking into account how other countries decided) and situational aspects (such as the COVID-19 pandemic).ConclusionsThere is good accordance between evidence-based recommendations and reimbursement decisions regarding hospital individual services in Austria. Beyond clinical evidence, organizational aspects seem to be considered often with regard to quality assurance but costs do not appear to play a major role. The Austrian system has mechanisms in place that can restrict widespread adoption of novel hospital individual services with uncertain clinical benefits. Future studies could investigate how well these mechanisms work and how they compare to other health systems in Europe.

Objectives: This systematic review aimed to assess mid-and long-term (at least 12 months) real-world study data from all types of spinal muscular atrophy (SMA) patients treated with any of the approved drugs or combination therapies.Methods: A systematic literature search was carried out in five databases. Two authors selected the studies based on pre-defined selection criteria and independently graded the risk of bias at study level.Results: Five hundred forty-six records were identified in the literature search and 22 studies (in 26 publications) were included in the analysis. Nusinersen, onasemnogene abeparvovec and combination therapies improved motor endpoints in SMA type 1 patients. SMA type 2 to type 4 patients treated with nusinersen showed stabilisation or small improvements in motor endpoints with some deterioration observed. Quality of life endpoints, such as respiratory and nutritional support were poorly reported on. Drug-related adverse events occurred rarely in all types of SMA patients with all assessed drugs. Mid-and long-term studies on risdiplam could not be identified.Conclusions: The large quantity of missing data and heterogeneity of studies hinder comparability. Although stability and further improvement on the long-term is still uncertain, the results from the included evidence, as well as from pivotal trials show a striking contrast to the natural progression of the disease.

Purpose The purpose of this systematic review is to evaluate whether self-expandable implantable vs non-self-expandable injectable bulking agents (second-line therapies) are equal/superior in terms of effectiveness (severity, quality of life [QoL]) and safety (adverse events) for faecal incontinence (FI). Methods A systematic review was conducted, and five databases were searched (Medline via Ovid, Embase, Cochrane Library, University of York Centre for Reviews and Dissemination, and International Network of Agencies for Health Technology database). In-/exclusion criteria were predefined according to the PICOS scheme. The Institute of Health Economics risk of bias (RoB) tool assessed studies' internal validity. According to the Grading of Recommendations, Assessment, Development and Evaluation approach, the strength of evidence for safety outcomes was rated. A qualitative synthesis of the evidence was used to analyse the data. Results The evidence consists of eight prospective single-arm, before-after studies (166 patients) fulfilling the inclusion criteria for assessing clinical effectiveness and safety of implantable bulking agents. FI severity statistically significantly improved in five of seven studies rated by the Cleveland Clinic FI Score and in three of five studies measured by the Vaizey score. Statistically significant improved disease-related QoL was found in one of five studies measured by the FI QoL Score and in one of two studies rated by the American Medical Systems score. Procedure-related adverse events occurred in 16 of 166 patients (i.e., intraoperative complications, anal discomfort and pain). Device-related adverse events occurred in 48 of 166 patients, including prostheses’ dislodgement and removed/extruded prostheses. Studies were judged with moderate/high RoB. The strength of evidence for safety was judged to be very low. Conclusion Implantable bulking agents might be an effective and safe minimally invasive option in FI treatment if conservative therapies fail. FI severity significantly improved, however, effects on QoL need to be explored in further studies. Due to the uncontrolled nature of the case series, comparative studies need to be awaited.

The history of the European cooperation on health technology assessment (HTA) has reached an important milestone with the adoption of the European HTA Regulation (HTA R) 2021/2282 in Dec 2021 (1). Its publication in the Official Journal of the European Union means a lot to those of us who wish to give HTA a stronger role in supporting health policy in favor of sustainable healthcare systems in Europe. The HTA R was prepared well by the European Commission with an impact assessment on policy options for enhanced EU cooperation on HTA (2) in 2017, followed by 3 years of negotiations with Member States. Now the ratified document stipulates that the European Cooperation on HTA will be based on a legal mandate and no longer stay a voluntary project-based initiative. It also means sustainability, since a permanent Secretariat at the European Commission will be set-up under the HTA R.