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Introduction: Health state valuation and diagnostic-therapeutic pathways at the junction between non-metastatic and metastatic castration-resistant prostate cancer (CRPC) are not well documented. We aimed at: (i) estimating the disability weights (DWs) for health states across a continuum of disease from asymptomatic non-metastatic (nmCRPC) to symptomatic metastatic state (mCRPC); (ii) mapping the diagnostic-therapeutic pathway of nmCRPC in Italy., Methods: Structured qualitative interviews were performed with clinical experts to gather information on nmCRPC clinical pathway. An online survey was administered to clinical experts to estimate DWs for four CRPC health states defined from interviews and literature review (i.e., nmCRPC, asymptomatic mCRPC, symptomatic mCRPC, mCRPC in progression during or after chemotherapy). Clinicians' preferences for health states were elicited using the Person-Trade-Off (PTO) and Visual Analogue Scale (VAS) methods. DWs associated with each health state, from 0 (best imaginable health state) and 1 (worst imaginable health state), were estimated., Results: We found that the management of nmCRPC is heterogeneous across Italian regions and hospitals, especially with respect to diagnostic imaging techniques. DWs for PTO ranged from 0.415 (95% confidence interval [CI] 0.208-0.623) in nmCRPC to 0.740 (95% CI 0.560-0.920) in mCRPC, in progression during or after chemotherapy. DWs for VAS ranged between 0.246 (95% CI 0.131-0.361) in nmCRPC to 0.689 (95% CI 0.583-0.795) in mCRPC, in progression during or after chemotherapy., Conclusions: Estimated DWs suggest that delaying transition to a metastatic state might ease the disease burden at both patient and societal levels., Competing Interests: Conflict of interest: LB, OC, RDV and GIR declare no potential conflicts of interest with respect to the research, authorship and publication of this study. MS declares the following competing interests: Janssen-Cilag SpA (consultations), Takeda (consultations). CDF, PB and IL are employees of Janssen-Cilag SpA., (Copyright © 2022, The Authors.)

Introduction: Using a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is, with shorter time, smaller sample size and lower cost. However, there is currently no consensus-driven guideline for the reporting of RCTs using a surrogate endpoint as a primary outcome; therefore, we seek to develop SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) extensions to improve the design and reporting of these trials. As an initial step, scoping and targeted reviews will identify potential items for inclusion in the extensions and participants to contribute to a Delphi consensus process., Methods and Analysis: The scoping review will search and include literature reporting on the current understanding, limitations and guidance on using surrogate endpoints in trials. Relevant literature will be identified through: (1) bibliographic databases; (2) grey literature; (3) handsearching of reference lists and (4) solicitation from experts. Data from eligible records will be thematically analysed into potential items for inclusion in extensions. The targeted review will search for RCT reports and protocols published from 2017 to 2021 in six high impact general medical journals. Trial corresponding author contacts will be listed as potential participants for the Delphi exercise., Ethics and Dissemination: Ethical approval is not required. The reviews will support the development of SPIRIT and CONSORT extensions for reporting surrogate primary endpoints (surrogate endpoint as the primary outcome). The findings will be published in open-access publications.This review has been prospectively registered in the OSF Registration DOI: 10.17605/OSF.IO/WP3QH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Randomised controlled trials (RCTs) may use surrogate endpoints as substitutes and predictors of patient-relevant/participant-relevant final outcomes (eg, survival, health-related quality of life). Translation of effects measured on a surrogate endpoint into health benefits for patients/participants is dependent on the validity of the surrogate; hence, more accurate and transparent reporting on surrogate endpoints is needed to limit misleading interpretation of trial findings. However, there is currently no explicit guidance for the reporting of such trials. Therefore, we aim to develop extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines to improve the design and completeness of reporting of RCTs and their protocols using a surrogate endpoint as a primary outcome., Methods and Analysis: The project will have four phases: phase 1 (literature reviews) to identify candidate reporting items to be rated in a Delphi study; phase 2 (Delphi study) to rate the importance of items identified in phase 1 and receive suggestions for additional items; phase 3 (consensus meeting) to agree on final set of items for inclusion in the extensions and phase 4 (knowledge translation) to engage stakeholders and disseminate the project outputs through various strategies including peer-reviewed publications. Patient and public involvement will be embedded into all project phases., Ethics and Dissemination: The study has received ethical approval from the University of Glasgow College of Medical, Veterinary and Life Sciences Ethics Committee (project no: 200210051). The findings will be published in open-access peer-reviewed publications and presented in conferences, meetings and relevant forums., Competing Interests: Competing interests: Sylwia Bujkiewicz has served as a paid consultant, providing methodological advice, to NICE, Roche and RTI Health Solutions, received payments for educational events from Roche and has received research funding from European Federation of Pharmaceutical Industries and Associations (EEPIA) and Johnson and Johnson. Mario Ouwens works for and has shares in AstraZeneca. Dr Joseph S Ross is an Associate Editor at BMJ and co-founder (unpaid) of medRxiv; Dr Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Food and Drug Administration for the Yale-Mayo Clinic Centre for Excellence in Regulatory Science and Innovation (CERSI) programme (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164 and R01HL144644), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; in addition, Dr Ross is an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Cancer and anticancer treatments can lead to several negative side effects, including malnutrition. Despite the recognized need for adequate nutritional support in cancer patients, in daily clinical practice, nutrition is still not considered one of the first aspects to be considered. Malnutrition negatively affects the clinical outcomes, treatment response, and overall survival of cancer patients. In this study, three of the most controversial issues related to malnutrition, which emerged during an Italian Consensus Conference, were addressed specifically for patients with head and neck as well as gastrointestinal cancer. The timing of nutritional evaluation and intervention, extension of the Enhanced Recovery after Surgery (ERAS ® ) protocols, and cost-effectiveness of nutritional interventions have been considered. This study aimed to illustrate the state-of-the art of each issue and hypothesize future perspectives and actions to be taken, trying to suggest a new nutritional management model for cancer patients in Italy that overcomes the critical issues encountered. Of note, the timely diagnosis of nutritional issue appears to be essential to ensure the correct management of malnourished cancer patients as well as those who are at high risk of malnutrition. Standardized protocols, screening tests, and the inclusion of nutritional parameters in patient medical records would help to achieve good clinical outcomes. Finally, appropriate nutritional support is also associated with cost savings, and it seems necessary to promote its clinical and economic value to obtain improvements in both outcomes and management costs., Competing Interests: PB reports advisory board or conference honoraria from Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Sun Pharma, Angelini, Molteni, Bristol-Myers Squibb, GSK, and Nestlé ED’A has served as scientific lecturer and/or advisory board and/or received unconditioned grants and/or participate to sponsored trials by Nestle Health Science, Merck spa, Astra Zeneca, Pfizer, and MSD. RC has served as scientific lecturer and/or consultant and/or on advisory panels for Baxter, Fresenius Kabi, BBraun Nestlé Health Science, and Nutricia and received unconditioned research grants by Nestlé Health Science The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2022 Bossi, De Luca, Ciani, D’Angelo and Caccialanza.)

Digital health and mobile medical apps (MMAs) have shown great promise in transforming health care, but their adoption in clinical care has been unsatisfactory, and regulatory guidance and coverage decisions have been lacking or incomplete. A multidimensional assessment framework for regulatory, policymaking, health technology assessment, and coverage purposes based on the MMA lifecycle is needed. A targeted review of relevant policy documents from international sources was conducted to map current MMA assessment frameworks, to formulate 10 recommendations, subsequently shared amongst an expert panel of key stakeholders. Recommendations go beyond economic dimensions such as cost and economic evaluation and also include MMA development and update, classification and evidentiary requirements, performance and maintenance monitoring, usability testing, clinical evidence requirements, safety and security, equity considerations, organizational assessment, and additional outcome domains (patient empowerment and environmental impact). The COVID-19 pandemic greatly expanded the use of MMAs, but temporary policies governing their use and oversight need consolidation through well-developed frameworks to support decision-makers, producers and introduction into clinical care processes, especially in light of the strong international, cross-border character of MMAs, the new EU medical device and health technology assessment regulations, and the Next Generation EU funding earmarked for health digitalization., (© 2022 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Health economists have written extensively on the design and implementation of coverage with evidence development (CED) schemes and have proposed theoretical frameworks based on cost-effectiveness modeling and value of information analysis. CED may aid decision-makers when there is uncertainty about the (cost-)effectiveness of a new health technology at the time of reimbursement. Medical devices are potential candidates for CED schemes, as regulatory regimes do not usually require the same level of efficacy and safety data normally needed for pharmaceuticals. The purpose of this research is to assess whether the actual practice of CED for medical devices in Europe meets the theoretical principles proposed by health economists and whether theory and practice can be more closely aligned. Based on decision-makers' perceptions of the challenges associated with CED schemes, plus examples from the schemes themselves, we discuss a series of proposals for assessing the desirability of schemes, their design, implementation, and evaluation. These proposals, while reflecting the practical challenges with developing CED programs, embody many of the principles suggested by economists and should support decision-makers in dealing with uncertainty about the real-world performance of devices., (© 2022 The Authors. Health Economics published by John Wiley & Sons Ltd.)

In the drive toward faster patient access to treatments, health technology assessment (HTA) agencies and payers are increasingly faced with reliance on evidence based on surrogate endpoints, increasing decision uncertainty. Despite the development of a small number of evaluation frameworks, there remains no consensus on the detailed methodology for handling surrogate endpoints in HTA practice. This research overviews the methods and findings of four empirical studies undertaken as part of COMED (Pushing the Boundaries of Cost and Outcome Analysis of Medical Technologies) program work package 2 with the aim of analyzing international HTA practice of the handling and considerations around the use of surrogate endpoint evidence. We have synthesized the findings of these empirical studies, in context of wider contemporary body of methodological and policy-related literature on surrogate endpoints, to develop a web-based decision tool to support HTA agencies and payers when faced with surrogate endpoint evidence. Our decision tool is intended for use by HTA agencies and their decision-making committees together with the wider community of HTA stakeholders (including clinicians, patient groups, and healthcare manufacturers). Having developed this tool, we will monitor its use and we welcome feedback on its utility., (© 2022 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Competing Interests: The authors declare no conflicts. Author disclosures are available in the supporting information.

Competing Interests: The authors declare no conflicts.

Competing Interests: Competing interests: None declared.

On 31st January 2020, the Italian cabinet declared a 6-month national emergency after the detection of the first two COVID-19 positive cases in Rome, two Chinese tourists travelling from Wuhan. Between then and the total lockdown introduced on 22nd March 2020 Italy was hit by an unprecedented crisis. In addition to being the first European country to be heavily swept by the COVID-19 pandemic, Italy was the first to introduce stringent lockdown measures. The SARS-CoV-2 outbreak and related COVID-19 pandemic have been the worst public health challenge endured in recent history by Italy. Two months since the beginning of the first wave, the estimated excess deaths in Lombardy, the hardest hit region in the country, reached a peak of more than 23,000 deaths. The extraordinary pressures exerted on the Italian Servizio Sanitario Nazionale (SSN) inevitably leads to questions about its preparedness and the appropriateness and effectiveness of responses implemented at both national and regional levels. The aim of the paper is to critically review the Italian response to the COVID-19 crisis spanning from the first early acute phases of the emergency (March-May 2020) to the relative stability of the epidemiological situation just before the second outbreak in October 2020.

Objectives: To test the feasibility of using videoconferencing (VC) administered interviews and to derive an EQ-5D-5L value set for Italy., Methods: Preferences were collected using the EuroQol standardized valuation protocol (EQ-VT) administered via VC. Two valuation methods were employed, composite time trade-off (cTTO) and discrete choice experiment (DCE). Technical, organizational and protocol feasibility were tested in a pilot of 198 interviews. Upon positive assessment, data collection continued with a target sample of 1000-1200 participants including the pilot. Quality control (QC) procedures were employed to monitor interviewers' performance during the pilot and the data collection. Data were modelled using GLS, Tobit, Logit and Hybrid models with different error specifications. Monotonicity of coefficients, statistical significance, and theoretical considerations informed the model choice., Results: Dropouts and technical problems occurred in less than 5% of the 198 pilot interviews. Protocol compliance was demonstrated with significant improvements in QC parameters and limited interviewers' effects, for all interviewers. Overall, interviewers were satisfied with this mode of administration, highlighting it allows flexibility and efficient scheduling. Based on these results, VC was deemed as a feasible mode of administration. The study collected preferences for 1182 responders, including the pilot interviews. The demographic characteristics of the sample were representative of the Italian general population for age, gender and geographical macro-areas. The hybrid Tobit heteroscedastic model without constant estimated on the full sample (including pilot) was selected for the derivation of the value set. Values ranged from -0.571 for the worst health state (55555) to 1 for the best health state (11111). Pain/discomfort registered the largest decrement, followed by mobility, anxiety/depression, self-care, and usual activities. 523 health states were worse than dead., Conclusions: VC is viable for the conduct of valuation interviews. The Italian value set for the EQ-5D-5L can be used for value determinations of health technologies., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Although nonfatal myocardial infarction (MI) is associated with an increased risk of mortality, evidence validating nonfatal MI as a surrogate end point for all-cause or cardiovascular (CV) mortality is lacking., Objective: To examine whether nonfatal MI may be a surrogate for all-cause or CV mortality in patients with or at risk for coronary artery disease., Data Sources: In this meta-analysis, PubMed was searched from inception until December 31, 2020, for randomized clinical trials of interventions to treat or prevent coronary artery disease reporting mortality and nonfatal MI published in 3 leading journals., Study Selection: Randomized clinical trials including at least 1000 patients with 24 months of follow-up., Data Extraction and Synthesis: Trial-level correlations between nonfatal MI and all-cause or CV mortality were assessed for surrogacy using the coefficient of determination (R2). The criterion for surrogacy was set at 0.8. Subgroup analyses based on study subject (primary prevention, secondary prevention, mixed primary and secondary prevention, and revascularization), era of trial (before 2000, 2000-2009, and 2010 and after), and follow-up duration (2.0-3.9, 4.0-5.9, and ≥6.0 years) were performed., Main Outcomes and Measures: All-cause or CV mortality and nonfatal MI., Results: A total of 144 articles randomizing 1 211 897 patients met the criteria for inclusion. Nonfatal MI did not meet the threshold for surrogacy for all-cause (R2 = 0.02; 95% CI, 0.00-0.08) or CV (R2 = 0.11; 95% CI, 0.02-0.27) mortality. Nonfatal MI was not a surrogate for all-cause mortality in primary (R2 = 0.01; 95% CI, 0.001-0.26), secondary (R2 = 0.03; 95% CI, 0.00-0.20), mixed primary and secondary prevention (R2 = 0.001; 95% CI, 0.00-0.08), or revascularization trials (R2 = 0.21; 95% CI, 0.002-0.50). For trials enrolling patients before 2000 (R2 = 0.22; 95% CI, 0.08-0.36), between 2000 and 2009 (R2 = 0.02; 95% CI, 0.00-0.17), and from 2010 and after (R2 = 0.01; 95% CI, 0.00-0.09), nonfatal MI was not a surrogate for all-cause mortality. Nonfatal MI was not a surrogate for all-cause mortality in randomized clinical trials with 2.0 to 3.9 (R2 = 0.004; 95% CI, 0.00-0.08), 4.0 to 5.9 (R2 = 0.06; 95% CI, 0.001-0.16), or 6.0 or more years of follow-up (R2 = 0.30; 95% CI, 0.01-0.55)., Conclusions and Relevance: The findings of this meta-analysis do not appear to establish nonfatal MI as a surrogate for all-cause or CV mortality in randomized clinical trials of interventions to treat or prevent coronary artery disease.

Background: There is currently limited evidence on the level and intensity of physical activity in individuals with hemophilia A. Mobile technologies can offer a rigorous and reliable alternative to support data collection processes but they are often associated with poor user retention. The lack of longitudinal continuity in their use can be partly attributed to the insufficient consideration of stakeholder inputs in the development process of mobile apps. Several user-centered models have been proposed to guarantee that a thorough knowledge of the end user needs is considered in the development process of mobile apps., Objective: The aim of this study is to design and validate an electronic patient-reported outcome mobile app that requires sustained active input by individuals during POWER, an observational study that aims at evaluating the relationship between physical activity levels and bleeding in patients with hemophilia A., Methods: We adopted a user-centered design and engaged several stakeholders in the development and usability testing of this mobile app. During the concept generation and ideation phase, we organized a need-assessment focus group (FG) with patient representatives to elicit specific design requirements for the end users. We then conducted 2 exploratory FGs to seek additional inputs for the app's improvement and 2 confirmatory FGs to validate the app and test its usability in the field through the mobile health app usability questionnaire., Results: The findings from the thematic analysis of the need-assessment FG revealed that there was a demand for sense making, for simplification of app functionalities, for maximizing integration, and for minimizing the feeling of external control. Participants involved in the later stages of the design refinement contributed to improving the design further by upgrading the app's layout and making the experience with the app more efficient through functions such as chatbots and visual feedback on the number of hours a wearable device had been worn, to ensure that the observed data were actually registered. The end users rated the app highly during the quantitative assessment, with an average mobile health app usability questionnaire score of 5.32 (SD 0.66; range 4.44-6.23) and 6.20 (SD 0.43; range 5.72-6.88) out of 7 in the 2 iterative usability testing cycles., Conclusions: The results of the usability test indicated a high, growing satisfaction with the electronic patient-reported outcome app. The adoption of a thorough user-centered design process using several types of FGs helped maximize the likelihood of sustained retention of the app's users and made it fit for data collection of relevant outcomes in the observational POWER study. The continuous use of the app and the actual level of engagement will be evaluated during the ongoing trial., Trial Registration: ClinicalTrials.gov NCT04165135; https://clinicaltrials.gov/ct2/show/NCT04165135., (©Francesco Petracca, Rosaria Tempre, Maria Cucciniello, Oriana Ciani, Elena Pompeo, Luigi Sannino, Valeria Lovato, Giancarlo Castaman, Alessandra Ghirardini, Rosanna Tarricone. Originally published in JMIR Formative Research (https://formative.jmir.org), 01.12.2021.)

Objectives: Medical devices are potentially good candidates for coverage with evidence development (CED) schemes, as clinical data at market entry are often sparse and (cost-)effectiveness depends on real-world use. The objective of this research was to explore the diffusion of CED schemes for devices in Europe, and the factors that favour or hamper their utilization., Methods: We conducted structured interviews with 25 decision-makers from 22 European countries to explore the characteristics of existing CED programmes for devices, and how decision makers perceived 13 pre-identified challenges associated with initiating and operating CED schemes for devices. We also collected data on individual schemes that were either initiated or still ongoing in the last 5 years., Results: We identified seven countries with CED programmes for devices and 78 ongoing schemes. The characteristics of CED programmes varied across countries, including eligibility criteria, roles and responsibilities of stakeholders, funding arrangements, and type of decisions being contemplated at the outset of each scheme. We observed a high variability in how decision makers perceived CED-related challenges possibly reflecting country-specific arrangements and different experiences with CED. One general finding across all countries was that relatively little attention was paid to the evaluation of schemes, both during and at their completion., Conclusions: CED programmes for devices with different characteristics exist in Europe. Decision-makers' perceptions differ on the challenges associated with these schemes. More exchange of knowledge and experience will help decision makers anticipate the likely challenges in CED schemes for devices, and to learn from good practices existing elsewhere., (© 2021. The Author(s).)

COVID-19 pandemic challenges have accelerated the reliance on digital health fuelling the expanded incorporation of mobile apps into healthcare services, particularly for the management of long-term conditions such as chronic diseases (CDs). However, the impact of health apps on outcomes for CD remains unclear, potentially owing to both the poor adoption of formal development standards in the design process and the methodological quality of studies. A systematic search of randomised trials was performed on Medline, ScienceDirect, the Cochrane Library and Scopus to provide a comprehensive outlook and review the impact of health apps on CD. We identified 69 studies on diabetes (n = 29), cardiovascular diseases (n = 13), chronic respiratory diseases (n = 13), cancer (n = 10) or their combinations (n = 4). The apps rarely adopted developmental factors in the design stage, with only around one-third of studies reporting user or healthcare professional engagement. Apps differed significantly in content, with a median of eight behaviour change techniques adopted, most frequently pertaining to the 'Feedback and monitoring' (91%) and 'Shaping knowledge' (72%) categories. As for the study methodologies, all studies adopted a traditional randomised control trial (RCT) design, with relatively short follow-ups and limited sample sizes. Findings were not significant for the majority of studies across all CD, with most RCTs revealing a high risk of bias. To support the adoption of apps for CD management, this review reinforces the need for more robust development and appropriate study characteristics to sustain evidence generation and elucidate whether study results reflect the true benefits of apps or a biased estimate due to unsuitable designs., (© 2021. The Author(s).)

Competing Interests: Competing interests: DD is an employee of NICE, funded by grants from the European Union’s IMI and Horizon 2020 research and innovation programme. SB has served as a paid consultant providing methodological advice to NICE, Roche and RTI Health Solutions. SB was supported by the Medical Research Council through the methodology research panel grants and has previously received research funding from European Federation of Pharmaceutical Industries & Associations (EFPIA) as part of unrelated European Union IMI GetReal project. HN previously received funding from the Pharmaceutical Group of the European Union for an unrelated systematic review on community pharmacists. HN currently receives funding from the Health Foundation on an unrelated project on pharmaceutical policy. OC received funding from the European Union’s Horizon 2020 research and innovation programme. The views expressed in this article are those of the authors and do not necessarily reflect those of their employers or funders. Provenance and peer review: Not commissioned; externally peer reviewed.

Objective: The assessment of benefits and harms from experimental treatments often ignores the association between outcomes. In a randomized trial, generalized pairwise comparisons (GPC) can be used to assess a Net Benefit that takes this association into account., Study Design and Settings: We use GPC to analyze a fictitious trial of treatment versus control, with a binary efficacy outcome (response) and a binary toxicity outcome, as well as data from two actual randomized trials in oncology. In all cases, we compute the Net Benefit for scenarios with different orders of priority between response and toxicity, and a range of odds ratios (ORs) for the association between these outcomes., Results: The GPC Net Benefit was quite different from the benefit/harm computed using marginal treatment effects on response and toxicity. In the fictitious trial using response as first priority, treatment had an unfavorable Net Benefit if OR < 1, but favorable if OR > 1. With OR = 1, the Net Benefit was 0. Results changed drastically using toxicity as first priority., Conclusion: Even in a simple situation, marginal treatment effects can be misleading. In contrast, GPC assesses the Net Benefit as a function of the treatment effects on each outcome, the association between outcomes, and individual patient priorities., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The paper discusses the responses to the COVID-19 crisis in the acute phase of the first wave of the pandemic (February-May 2020) by different Italian regions in Italy, which has a decentralised healthcare system. We consider five regions (Lombardy, Veneto, Emilia-Romagna, Umbria, Apulia) which are located in the north, centre and south of Italy. These five regions differ both in their healthcare systems and in the extent to which they were hit by the first wave of COVID-19 pandemic. We investigate their different responses to COVID-19 reflecting on seven management factors: (1) monitoring, (2) learning, (3) decision-making, (4) coordinating, (5) communicating, (6) leading, and (7) recovering capacity. In light of these factors, we discuss the analogies and differences among the regions and their different institutional choices., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Introduction : The unparalleled surge in digital health adoption during the COVID-19 pandemic has emphasized the potential of mHealth apps. However, the quality of available evidence is generally low, and regulatory frameworks have focused on apps with medical purposes only, overlooking apps with significant interactions with patients that may require stronger oversight. Areas covered : To support this expanded evidence generation process, we identified the reasons that distinguish mHealth apps compared to medical devices at large and that should differentially feature their assessment. mHealth apps are characterized by the iterative nature of the corresponding interventions, frequent user interactions with a non-linear relationship between technology usage, engagement and outcomes, significant organizational implications, as well as challenges associated with genericization, their broad diagnostic potential, and price setting. Expert Opinion : The renewed reliance experienced during the pandemic and the unprecedented injection of resources through recovery instruments can further boost the development of apps. Only robust evidence of the benefits of mHealth apps will persuade health-care professionals and beneficiaries to systematically deploy them. Regulatory bodies will need to question their current approaches by adopting comprehensive evaluation processes that adequately consider the specific features of mHealth apps.

Objective: There is no comprehensive assessment of which patient-reported outcomes (PROs) are recommended in core outcome sets (COS), and how they should be measured. The aims of this study are to review COS that include patient-reported outcomes measures (PROMs), identify their target health domains, main characteristics, and their overlap within and across different disease areas., Study Design and Setting: We selected COS studies collected in a publicly available database that included at least one recommended PROM. We gathered information on study setting, disease area, and targeted outcome domains. Full-text of recommended instruments were obtained, and an analysis of their characteristics and content performed. We classified targeted domains according to a predefined 38-item taxonomy., Results: Overall, we identified 94 COS studies that recommended 323 unique instruments, of which: 87% were included in only one COS; 77% were disease-specific; 1.5% preference-based; and 61% corresponded to a full questionnaire. Most of the instruments covered broad health-related constructs, such as global quality of life (25%), physical functioning (22%), emotional functioning and wellbeing (7%)., Conclusion: The wealth of recommended instruments observed even within disease areas does not fit with a vision of systematic, harmonized collection of PROM data in COS within and across disease areas., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: A recent debate in health economics and outcomes research community identified option value as one of the elements warranting consideration in the assessment of medical technologies. To conduct a scoping review of contributions on option value in the healthcare sector and identify relevant conceptual aspects and methods used to incorporate it in standard economic evaluations., Methods: A systematic search was conducted up to July 2020 to identify contributions from electronic bibliographic database and gray literature. Data on the proposed definitions of option value, theoretical implications of its use in economic evaluations, and methods used to estimate it were extracted and analyzed., Results: We found 57 eligible studies. Three different definitions emerged: insurance value, real option value, and option value of survival. Focusing on the latter (24 studies), we analyzed in depth 8 empirical applications across 7 therapeutic areas. The most relevant methodological challenges were on the perspective used in economic evaluations and how to robustly manage forecasting uncertainty, update cost-effectiveness thresholds, and avoid double-counting issues. For empirical studies assessing the total value of the technology, including option value, estimates ranged from +7% to +469% of its conventional value., Conclusions: This review synthesizes theoretical and empirical aspects on option value of healthcare technologies and proposes a terminology to distinguish 3 different concepts identified. Future work should focus primarily on agreeing on whether option value should be included in economic evaluations and, if so, on developing and validating reliable methods for its ex-ante estimation., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objective: There is limited evidence regarding the economic effects of nutrition support in cancer patients. This study aims at investigating the cost-effectiveness profile of systematic oral nutritional supplementation (ONS) in head and neck cancer (HNC) patients undergoing radiotherapy (RT) and receiving nutritional counseling., Methods: A cost-effectiveness analysis based on a RCT was performed to estimate direct medical costs, life years gained (LYG) and Quality-Adjusted Life Years (QALY) for nutritional counseling with or without ONS at 5-month and 6-year follow up time. Value of information analysis was performed to value the expected gain from reducing uncertainty through further data collection., Results: ONS with nutritional counseling produced higher QALY than nutritional counseling alone (0.291 ± 0.087 vs 0.288 ± 0.087), however the difference was not significant (0.0027, P = 0.84). Mean costs were €987.60 vs €996.09, respectively in the treatment and control group (-€8.96, P = 0.98). The Incremental Cost Effectiveness Ratio (ICER) was -€3,277/QALY, with 55.4% probabilities of being cost-effective at a cost-effectiveness threshold of €30,000/QALY. The Expected Incremental Benefit was €95.16 and the Population Expected Value of Perfect Information was €8.6 million, implying that additional research is likely to be worthwhile. At a median 6-year follow up, the treatment group had a significantly better survival rate when adjusting for late effect (P = 0.039)., Conclusion: Our findings provide the first evidence to inform decisions about funding and reimbursement of ONS in combination with nutritional counseling in HNC patients undergoing RT. ONS may improve quality of cancer care at no additional costs, however further research on the cost-effectiveness of nutritional supplementation is recommended., Trial Registration: ClinicalTrials.gov: NCT02055833. Registered 5th February 2014 https://clinicaltrials.gov/ct2/show/NCT02055833.

Differing contexts have greatly influenced HTA development in various countries, with considerable effort recently made by international HTA networks (e.g., EUnetHTA) and the European Union (EU) to make HTA a more coherent, equal, and efficient process. Medical devices (MDs) present particular challenges for HTA because of frequent, rapid innovation, outcomes influenced by end-user competence, dynamic pricing and often low-quality scientific evidence. Our objective is to describe the development, structure and governance of a National HTA Program for MDs (PNHTADM) in Italy, a highly participatory, stakeholder-engaged, evidence-based process to reform a fragmented system of appraisal and approval. Based largely on EUnetHTA methods, the resulting process delineates a standardized system for proposing MDs by any stakeholders, accrediting HTA producers, setting criteria for prioritization and appraisals, and innovatively linking recommendations with coverage, reimbursement and procurement of MDs. Expected benefits include reduced disparities in pricing and reimbursement policies and improved access to new technologies across 21 regional healthcare systems in Italy's decentralized, universal system, complete with provisions to require additional evidence collection and centrally monitor diffusion. Though devised for Italy, the design, resources and underlying analysis provide a framework for other nations seeking to consolidate HTA initiatives, particularly in light of new EU regulation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier B.V.)

Background: Surrogate endpoints (i.e., intermediate endpoints intended to predict for patient-centered outcomes) are increasingly common. However, little is known about how surrogate evidence is handled in the context of health technology assessment (HTA)., Objectives: 1) To map methodologies for the validation of surrogate endpoints and 2) to determine their impact on acceptability of surrogates and coverage decisions made by HTA agencies., Methods: We sought HTA reports where evaluation relied on a surrogate from 8 HTA agencies. We extracted data on the methods applied for surrogate validation. We assessed the level of agreement between agencies and fitted mixed-effects logistic regression models to test the impact of validation approaches on the agency's acceptability of the surrogate endpoint and their coverage recommendation., Results: Of the 124 included reports, 61 (49%) discussed the level of evidence to support the relationship between the surrogate and the patient-centered endpoint, 27 (22%) reported a correlation coefficient/association measure, and 40 (32%) quantified the expected effect on the patient-centered outcome. Overall, the surrogate endpoint was deemed acceptable in 49 (40%) reports ( k -coefficient 0.10, P = 0.004). Any consideration of the level of evidence was associated with accepting the surrogate endpoint as valid (odds ratio [OR], 4.60; 95% confidence interval [CI], 1.60-13.18, P = 0.005). However, we did not find strong evidence of an association between accepting the surrogate endpoint and agency coverage recommendation (OR, 0.71; 95% CI, 0.23-2.20; P = 0.55)., Conclusions: Handling of surrogate endpoint evidence in reports varied greatly across HTA agencies, with inconsistent consideration of the level of evidence and statistical validation. Our findings call for careful reconsideration of the issue of surrogacy and the need for harmonization of practices across international HTA agencies.

Aim: Technological and computational advancements offer new tools for the collection and analysis of real-world data (RWD). Considering the substantial effort and resources devoted to collecting RWD, a greater return would be achieved if real-world evidence (RWE) was effectively used to support Health Technology Assessment (HTA) and decision making on medical technologies. A useful question is: To what extent are RWD suitable for generating RWE?, Methods: We mapped existing RWD sources in Europe for three case studies: hip and knee arthroplasty, transcatheter aortic valve implantation (TAVI) and mitral valve repair (TMVR), and robotic surgery procedures. We provided a comprehensive assessment of their content and appropriateness for conducting the HTA of medical devices. The identification of RWD sources was performed combining a systematic search on PubMed with gray literature scoping, covering fifteen European countries., Results: We identified seventy-one RWD sources on arthroplasties; ninety-five on TAVI and TMVR; and seventy-seven on robotic procedures. The number, content, and integrity of the sources varied dramatically across countries. Most sources included at least one health outcome (97.5%), with mortality and rehospitalization/reoperation the most common; 80% of sources included resource outcomes, with length of stay the most common, and comparators were available in almost 70% of sources., Conclusions: RWD sources bear the potential for the HTA of medical devices. The main challenges are data accessibility, a lack of standardization of health and economic outcomes, and inadequate comparators. These findings are crucial to enabling the incorporation of RWD into decision making and represent a readily available tool for getting acquainted with existing information sources.

Objectives: Methodological challenges in the evaluation of medical devices (MDs) may be different for early and late technology adopter countries, as well as the potential health technology assessment (HTA) solutions to tackle them. This study aims to provide guidance to Central and Eastern European (CEE) countries on how to address key challenges of HTA for MDs with special focus on the transferability of scientific evidence. Methods: As part of the COMED Horizon 2020 project, a comprehensive list of issues related to MD HTA were identified based on a targeted literature review. Health technology assessment issues which pose a greater challenge or require different solutions in late technology adopter countries were selected. Draught recommendations to address these issues were developed and discussed in a focus group. The recommendations were then validated with a wider group of experts, including HTA and reimbursement decision makers from CEE countries in May and June 2020. Results: A consolidated list of 11 recommendations were developed in 3 major areas: (1) clinical value assessment, focusing on the use of joint EU work, relying on real-world evidence, use of coverage with evidence development schemes, transferring evidence from foreign countries and addressing the challenges of learning curve and centre effect; (2) economic value assessment, covering cost calculation of complex medical devices and transferability of economic evaluations of MDs; (3) HTA processes, related to the frequent product modifications and various indications of MDs. Conclusions: Central and Eastern European countries with limited resources for conducting HTA, can benefit from HTA methods and evidence generated in early technology adopter countries. Considering the appropriate reuse of international HTA materials, late technology adopter countries can still implement HTA, even for MDs, which have a more limited evidence base compared with pharmaceuticals., Competing Interests: RD-B, SK, AZ, and ZK were employed by Syreon Research Institute. MH is self-employed in HTA/EBM Consulting Centre and has not received any remuneration of funding from the COMED project, nor has any commercial or financial relationship that could be construed as a potential conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Daubner-Bendes, Kovács, Niewada, Huic, Drummond, Ciani, Blankart, Mandrik, Torbica, Yfantopoulos, Petrova, Holownia-Voloskova, Taylor, Al, Piniazhko, Lorenzovici, Tarricone, Zemplényi and Kaló.)

A common development observed during the COVID-19 pandemic is the renewed reliance on digital health technologies. Prior to the pandemic, the uptake of digital health technologies to directly strengthen public health systems had been unsatisfactory; however, a relentless acceleration took place within health care systems during the COVID-19 pandemic. Therefore, digital health technologies could not be prescinded from the organizational and institutional merits of the systems in which they were introduced. The Italian National Health Service is strongly decentralized, with the national government exercising general stewardship and regions responsible for the delivery of health care services. Together with the substantial lack of digital efforts previously, these institutional characteristics resulted in delays in the uptake of appropriate solutions, territorial differences, and issues in engaging the appropriate health care professionals during the pandemic. An in-depth analysis of the organizational context is instrumental in fully interpreting the contribution of digital health during the pandemic and providing the foundation for the digital reconstruction of what is to come after., (©Francesco Petracca, Oriana Ciani, Maria Cucciniello, Rosanna Tarricone. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 30.12.2020.)

In the drive towards faster patient access to treatments, health technology assessment (HTA) agencies are increasingly faced with reliance on evidence from surrogate endpoints, leading to increased decision uncertainty. This study undertook an updated survey of methodological guidance for using surrogate endpoints across international HTA agencies. We reviewed HTA and economic evaluation methods guidance from European, Australian and Canadian HTA agencies. We considered how guidelines addressed the methods for handling surrogate endpoints, including (1) level of evidence, (2) methods of validation, and (3) thresholds of acceptability. Across the 73 HTA agencies surveyed, 29 (40%) had methodological guidelines that made specific reference to consideration of surrogate outcomes. Of the 45 methods documents analysed, the majority [27 (60%)] were non-technology specific, 15 (33%) focused on pharmaceuticals and three (7%) on medical devices. The principles of the European network for Health Technology Assessment (EUnetHTA) guidelines published in 2015 on the handling of surrogate endpoints appear to have been adopted by many European HTA agencies, i.e. preference for final patient-relevant outcomes and reliance on surrogate endpoints with biological plausibility and epidemiological evidence of the association between the surrogate and final endpoint. Only a small number of HTA agencies (UK National Institute for Care and Excellence; the German Institute for Medical Documentation and Information and Institute for Quality and Efficiency in Health Care; the Australian Pharmaceutical Benefits Advisory Committee; and the Canadian Agency for Drugs and Technologies in Health) have developed more detailed prescriptive criteria for the acceptance of surrogate endpoints, e.g. meta-analyses of randomised controlled trials showing strong association between the treatment effect on the surrogate and final outcomes. As the decision uncertainty associated with reliance on surrogate endpoints carries a risk to patients and society, there is a need for HTA agencies to develop more detailed methodological guidance for consistent selection and evaluation of health technologies that lack definitive final patient-relevant outcome evidence at the time of the assessment.

Introduction: The new European Union (EU) Regulations on medical devices and on in vitro diagnostics provide manufacturers and Notified Bodies with new tools to improve pre-market and post-market clinical evidence generation especially for high-risk products but fail to indicate what type of clinical evidence is appropriate at each stage of the whole lifecycle of medical devices. In this paper we address: i) the appropriate level and timing of clinical evidence throughout the lifecycle of high-risk implantable medical devices; and ii) how the clinical evidence generation ecosystem could be adapted to optimize patient access., Areas Covered: The European regulatory and health technology assessment (HTA) contexts are reviewed, in relation to the lifecycle of high-risk medical devices and clinical evidence generation recommended by international network or endorsed by regulatory and HTA agencies in different jurisdictions., Expert Opinion: Four stages are relevant for clinical evidence generation: i) pre-clinical, pre-market; ii) clinical, pre-market; iii) diffusion, post-market; and iv) obsolescence & replacement, post-market. Each stage has its own evaluation needs and specific studies are recommended to generate the appropriate evidence. Effective lifecycle planning requires anticipation of what evidence will be needed at each stage.

Competing Interests: Conflict of interest: The authors declare no conflict of interest.

Surrogate endpoints play an important role in drug development when they can be used to measure treatment effect early compared to the final clinical outcome and to predict clinical benefit or harm. Such endpoints are assessed for their predictive value of clinical benefit by investigating the surrogate relationship between treatment effects on the surrogate and final outcomes using meta-analytic methods. When surrogate relationships vary across treatment classes, such validation may fail due to limited data within each treatment class. In this paper, two alternative Bayesian meta-analytic methods are introduced which allow for borrowing of information from other treatment classes when exploring the surrogacy in a particular class. The first approach extends a standard model for the evaluation of surrogate endpoints to a hierarchical meta-analysis model assuming full exchangeability of surrogate relationships across all the treatment classes, thus facilitating borrowing of information across the classes. The second method is able to relax this assumption by allowing for partial exchangeability of surrogate relationships across treatment classes to avoid excessive borrowing of information from distinctly different classes. We carried out a simulation study to assess the proposed methods in nine data scenarios and compared them with subgroup analysis using the standard model within each treatment class. We also applied the methods to an illustrative example in colorectal cancer which led to obtaining the parameters describing the surrogate relationships with higher precision., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.)

Background: A Core Outcomes Set (COS) is an agreed minimum set of outcomes that should be reported in all clinical studies related to a specific condition. Using prostate cancer as a case study, we identified, summarized, and critically appraised published COS development studies and assessed the degree of overlap between them and selected real-world data (RWD) sources., Methods: We conducted a scoping review of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database to identify all COS studies developed for prostate cancer. Several characteristics (i.e., study type, methods for consensus, type of participants, outcomes included in COS and corresponding measurement instruments, timing, and sources) were extracted from the studies; outcomes were classified according to a predefined 38-item taxonomy. The study methodology was assessed based on the recent COS-STAndards for Development (COS-STAD) recommendations. A 'mapping' exercise was conducted between the COS identified and RWD routinely collected in selected European countries., Results: Eleven COS development studies published between 1995 and 2017 were retrieved, of which 8 were classified as 'COS for clinical trials and clinical research', 2 as 'COS for practice' and 1 as 'COS patient reported outcomes'. Recommended outcomes were mainly categorized into 'mortality and survival' (17%), 'outcomes related to neoplasm' (18%), and 'renal and urinary outcomes' (13%) with no relevant differences among COS study types. The studies generally fulfilled the criteria for the COS-STAD 'scope specification' domain but not the 'stakeholders involved' and 'consensus process' domains. About 72% overlap existed between COS and linked administrative data sources, with important gaps. Linking with patient registries improved coverage (85%), but was sometimes limited to smaller follow-up patient groups., Conclusions: This scoping review identified few COS development studies in prostate cancer, some quite dated and with a growing level of methodological quality over time. This study revealed promising overlap between COS and RWD sources, though with important limitations; linking established, national patient registries to administrative data provide the best means to additionally capture patient-reported and some clinical outcomes over time. Thus, increasing the combination of different data sources and the interoperability of systems to follow larger patient groups in RWD is required.

Purpose: This paper presents a comparative analysis of value-based frameworks (VBFs) developed in the United States and Europe for both drugs and medical devices., Methods: The authors relied on a comprehensive literature review to identify relevant dimensions of analysis and available VBFs. Compared to previous studies on this topic, this study focused on the roles and strategic objectives of different institutions and organizations currently orchestrating the debate and development of VBFs and value-based initiatives., Findings: Among several projects and initiatives aimed at measuring value in health care, the study identified and analyzed in detail 7 VBFs. Different frameworks not only reflect different conceptions of value, but also different strategic objectives for which value needs to be measured: influencing clinical decision making, informing health care policies, affecting reimbursement, and pricing mechanisms or driving industry developments. Ultimately, all of these objectives represent different levers for fostering value-based treatment choices, but their different routes imply the assignment of key responsibilities to different actors within health care: medical professionals, patients, policymakers, payers, and medical technology and pharmaceutical companies., Implications: The proliferation of frameworks used for measuring the value of different health care objects and processes seems certainly a worthy exercise, but a real paradigm shift toward value-based care could only happen if these tools will be systematically used in practice and if all of these levers are played together, with joint actions and shared awareness of the key stakeholders' groups., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Patient-reported outcomes (PROs) are any report of the status of a patient's health condition that comes directly from the patient (or in some cases from a caregiver or surrogate responder), without interpretation by a practitioner or anyone else. PROs are increasingly used as a valuable source of data in different domains of health care, including research, clinical practice, health care management, and decision making on the regulation, coverage, and reimbursement of new technologies. Several factors must be considered when selecting which PRO measure to use to ensure their appropriate use and interpretation as well as their relevance for decision makers. The increasing availability of PRO data, its integration with other data sources, and the improvements in data analytics offer a valuable opportunity to place the patient at the center of any health care process. However, several issues need to be addressed, including interoperability, data governance, security, privacy, and ethics, to realize an effective, integrated, standardized, real-time assessment of PROs in the health care systems., (Copyright © 2020. Published by Elsevier Inc.)

Background: Current national and international guidelines on the management of heart failure (HF) recommend exercise-based cardiac rehabilitation (ExCR), but do not differentiate this recommendation according to patient subgroups., Objectives: (1) To obtain definitive estimates of the impact of ExCR interventions compared with no exercise intervention (control) on mortality, hospitalisation, exercise capacity and health-related quality of life (HRQoL) in HF patients; (2) to determine the differential (subgroup) effects of ExCR in HF patients according to their age, sex, left ventricular ejection fraction, HF aetiology, New York Heart Association class and baseline exercise capacity; and (3) to assess whether or not the change in exercise capacity mediates for the impact of the ExCR on final outcomes (mortality, hospitalisation and HRQoL), and determine if this is an acceptable surrogate end point., Design: This was an individual participant data (IPD) meta-analysis., Setting: An international literature review., Participants: HF patients in randomised controlled trials (RCTs) of ExCR., Interventions: ExCR for at least 3 weeks compared with a no-exercise control, with 6 months' follow-up., Main Outcome Measures: All-cause and HF-specific mortality, all-cause and HF-specific hospitalisation, exercise capacity and HRQoL., Data Sources: IPD from eligible RCTs., Review Methods: RCTs from the Exercise Training Meta-Analysis of Trials for Chronic Heart Failure (ExTraMATCH/ExTraMATCH II) IPD meta-analysis and a 2014 Cochrane systematic review of ExCR (Taylor RS, Sagar VA, Davies EJ, Briscoe S, Coats AJ, Dalal H, et al . Exercise-based rehabilitation for heart failure. Cochrane Database Syst Rev 2014; 4 :CD003331)., Results: Out of the 23 eligible RCTs (4398 patients), 19 RCTs (3990 patients) contributed data to this IPD meta-analysis. There was a wide variation in exercise programme prescriptions across included studies. Compared with control, there was no statistically significant difference in pooled time-to-event estimates in favour of ExCR, although confidence intervals (CIs) were wide: all-cause mortality had a hazard ratio (HR) of 0.83 (95% CI 0.67 to 1.04); HF-related mortality had a HR of 0.84 (95% CI 0.49 to 1.46); all-cause hospitalisation had a HR of 0.90 (95% CI 0.76 to 1.06); and HF-related hospitalisation had a HR of 0.98 (95% CI 0.72 to 1.35). There was a statistically significant difference in favour of ExCR for exercise capacity and HRQoL. Compared with the control, improvements were seen in the 6-minute walk test (6MWT) (mean 21.0 m, 95% CI 1.57 to 40.4 m) and Minnesota Living with Heart Failure Questionnaire score (mean -5.94, 95% CI -1.0 to -10.9; lower scores indicate improved HRQoL) at 12 months' follow-up. No strong evidence for differential intervention effects across patient characteristics was found for any outcomes. Moderate to good levels of correlation ( R 2 trial O p  > 0.50) between peak oxygen uptake ( V O 2 peak) or the 6MWT with mortality and HRQoL were seen. The estimated surrogate threshold effect was an increase of 1.6 to 4.6 ml/kg/minute for V O 2 peak., Limitations: There was a lack of consistency in how included RCTs defined and collected the outcomes: it was not possible to obtain IPD from all includable trials for all outcomes and patient-level data on exercise adherence was not sought., Conclusions: In comparison with the no-exercise control, participation in ExCR improved the exercise and HRQoL in HF patients, but appeared to have no effect on their mortality or hospitalisation. No strong evidence was found of differential intervention effects of ExCR across patient characteristics. V O 2 peak and 6MWT may be suitable surrogate end points for the treatment effect of ExCR on mortality and HRQoL in HF. Future studies should aim to achieve a consensus on the definition of outcomes and promote reporting of a core set of HF data. The research team also seeks to extend current policies to encourage study authors to allow access to RCT data for the purpose of meta-analysis., Study Registration: This study is registered as PROSPERO CRD42014007170., Funding: The National Institute for Health Research Health Technology Assessment programme., Competing Interests: Rod S Taylor is currently co-chief investigator on a National Institute for Health Research (NIHR)-funded programme grant designing and evaluating the clinical effectiveness and cost-effectiveness of a home-based cardiac rehabilitation intervention for patients who have experienced heart failure (RP-PG-1210-12004). He is also a member of the NIHR Priority Research Advisory Methodology Group (August 2015–present). Previous roles include the NIHR South West Research for Patient Benefit Committee South West (2010–14); core group of methodological experts for the NIHR Programme Grants for Applied Research programme (2013–October 2017); NIHR Health Technology Assessment (HTA) Themed Call Board (2012–14); NIHR HTA General Board (2014–June 2017); and chairperson of the NIHR Health Services and Delivery Research Researcher-led Panel (March 2014–February 2018).

Background: Previous systematic reviews have indicated that exercise-based cardiac rehabilitation (ExCR) for patients with heart failure (HF) has a beneficial effect on health-related quality-of-life (HRQoL) and exercise capacity. However, there is uncertainty regarding potential differential effects of ExCR across HF patient subgroups., Objectives: The authors sought to undertake an individual participant data (IPD) meta-analysis to: 1) assess the impact of ExCR on HRQoL and exercise capacity in patients with HF; and 2) investigate differential effects of ExCR according to a range of patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischemic etiology, ejection fraction, and exercise capacity., Methods: A single dataset was produced, comprising randomized trials where ExCR (delivered for 3 weeks or more) was compared with a no exercise control group. Each trial provided IPD on HRQoL or exercise capacity (or both), with follow-up of 6 months or more. One- and 2-stage meta-analysis models were used to investigate the effect of ExCR overall and the interactions between ExCR and participant characteristics., Results: IPD was obtained from 13 trials for 3,990 patients, predominantly (97%) with reduced ejection fraction HF. Compared with the control group, there was a statistically significant difference in favor of ExCR for HRQoL and exercise capacity. At 12-month follow-up, improvements were seen in 6-min walk test (mean 21.0 m; 95% confidence interval: 1.57 to 40.4 m; p = 0.034) and Minnesota Living With HF score (mean improvement 5.9; 95% confidence interval: 1.0 to 10.9; p = 0.018). No consistent evidence was found of differential intervention effects across patient subgroups., Conclusions: These results, based on an IPD meta-analysis of randomized trials, confirm the benefit of ExCR on HRQoL and exercise capacity and support the Class I recommendation of current international clinical guidelines that ExCR should be offered to all HF patients. (Exercise Training for Chronic Heart Failure [ExTraMATCH II]: protocol for an individual participant data meta-analysis; PROSPERO: international database of systematic reviews CRD42014007170)., (Copyright © 2019. Published by Elsevier Inc.)

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., Competing Interests: Competing interests: OC, MC, FP, RT report grant from Helsinn Healthcare SA, during the conduct of the study; and are currently involved in the COMED H2020 EU project nr 779306. GA, NZ, MG report grant from Università Bocconi, during the conduct of the study. EN reports grants from Horizon2020 funding from the European Commission for IMPACT HTA project, personal fees from Dolon Consultancy, personal fees from previous consultancy and teaching activities, outside the submitted work. SN reports personal fees as speaker bureau from BMS, MSD, Takeda, BI, Roche, AstraZeneca, Eli Lillly, outside the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To undertake an individual patient data (IPD) meta-analysis to assess the impact of exercise-based cardiac rehabilitation (ExCR) in patients with heart failure (HF) on mortality and hospitalisation, and differential effects of ExCR according to patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischaemic aetiology, ejection fraction, and exercise capacity., Methods and Results: Randomised trials of exercise training for at least 3 weeks compared with no exercise control with 6-month follow-up or longer, providing IPD time to event on mortality or hospitalisation (all-cause or HF-specific). IPD were combined into a single dataset. We used Cox proportional hazards models to investigate the effect of ExCR and the interactions between ExCR and participant characteristics. We used both two-stage random effects and one-stage fixed effect models. IPD were obtained from 18 trials including 3912 patients with HF with reduced ejection fraction. Compared to control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals (CIs) were wide [all-cause mortality: hazard ratio (HR) 0.83, 95% CI 0.67-1.04; HF-specific mortality: HR 0.84, 95% CI 0.49-1.46; all-cause hospitalisation: HR 0.90, 95% CI 0.76-1.06; and HF-specific hospitalisation: HR 0.98, 95% CI 0.72-1.35]. No strong evidence was found of differential intervention effects across patient characteristics., Conclusion: Exercise-based cardiac rehabilitation did not have a significant effect on the risk of mortality and hospitalisation in HF with reduced ejection fraction. However, uncertainty around effect estimates precludes drawing definitive conclusions., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: Trans-arterial radio-embolization (TARE) is an emerging treatment for the management of hepatocellular carcinoma (HCC). TARE may compete with systemic chemotherapy, sorafenib, in intermediate stage patients with prior chemoembolization failure or advanced patients with tumoral macrovascular invasion with no extra-hepatic spread and good liver function. We performed a budget impact analysis (BIA) evaluating the expected changes in the expenditure for the Italian Healthcare Service within scenarios of increased utilization of TARE in place of sorafenib over the next five years., Methods: Starting from patient level data from three oncology centres in Italy, a Markov model was developed to project on a lifetime horizon survivals and costs associated to matched cohorts of intermediate-advanced HCC patients treated with TARE or sorafenib. The initial model has been integrated with epidemiological data to perform a BIA comparing the current scenario with 20 and 80% utilization rates for TARE and sorafenib, respectively, with increasing utilization rates of TARE of 30, 40 and 50% over the next 1, 3 and 5 years., Results: Compared to the current scenario, progressively increasing utilization rates of TARE over sorafenib in the next 5 years is expected to save globally about 7 million Euros., Conclusions: Radioembolization can be considered a valuable treatment option for patients with intermediate-advanced HCC. These findings enrich the evidence about the economic sustainability of TARE in comparison to standard systemic chemotherapy within the context of a national healthcare service.

Objectives: This study sought to validate exercise capacity (EC) as a surrogate for mortality, hospitalization, and health-related quality of life (HRQOL)., Background: EC is often used as a primary outcome in exercise-based cardiac rehabilitation (CR) trials of heart failure (HF) via direct cardiorespiratory assessment of maximum oxygen uptake (Vo 2 peak) or through submaximal tests, such as the 6-min walk test (6MWT)., Methods: After a systematic review, 31 randomized trials of exercise-based CR compared with no exercise control (4,784 HF patients) were included. Outcomes were pooled using random effects meta-analyses, and inverse variance weighted linear regression equations were fitted to estimate the relationship between the CR on EC and all-cause mortality, hospitalization, and HRQOL. Spearman correlation coefficient (ρ), R 2 at trial level, and surrogate threshold effect (STE) were calculated. STE represents the intercept of the prediction band of the regression line with null effect on the final outcome., Results: Exercise-based CR is associated with positive effects on EC measured through Vo 2 peak (+3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (+41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (Vo 2 peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R 2  <52%; |ρ| < 0.72). Estimated STE was an increase of 5 ml/kg/min for Vo 2 peak and 80 m for 6MWT to predict a significant improvement in HRQOL., Conclusions: The study results indicate that EC is a poor surrogate endpoint for mortality and hospitalization but has moderate validity as a surrogate for HRQOL. Further research is needed to confirm these findings across other HF interventions., (Copyright © 2018. Published by Elsevier Inc.)

Background: Fenestrated endovascular aneurysm repair (fEVAR) is a new approach for complex abdominal aortic aneurysms, limited to a few specialist centers, with limited evidence base. We developed a cost-effectiveness decision model of fEVAR compared to open surgical repair (OSR) to investigate the likely direction of costs and benefits and inform further research projects on this technology., Methods: A systematic review with meta-analysis and a four-state Markov model were used to estimate the cost-effectiveness of fEVAR versus OSR. We used a recent coverage with evidence development framework to characterize the main sources of uncertainty and inform decisions about the type of further research that would be most worthwhile and feasible., Results: Seven observational comparative studies were identified, of which four presented odds ratios adjusted for confounders. The odds ratios for operative mortality varied widely between studies. Assuming a central estimate of the odds ratio of 0.54 (95% CI 0.05-6.24), the decision model estimated that the incremental cost per quality adjusted life year (QALY) was £74,580/QALY with a probability of 9 and 16% of being cost-effective at standard cost-effectiveness thresholds of £20,000/QALY and £30,000/QALY, respectively. The Expected Value of Perfect Information over 10 years at a threshold of £20,000/QALY was £11.2 million. Operative mortality contributed to most of the uncertainty in the decision model., Conclusions: In the case of "maturing technologies", decision modelling indicates the likely direction of costs and benefits and guides the development of further research projects. In our analysis of fEVAR versus OSR, decision uncertainty, particularly around operative mortality, might be effectively resolved by a short-term RCT, or possibly a well-conducted comparative observational study. Decision makers may consider that a conditional coverage decision is warranted with assessments required to make this type of recommendation depending on local priorities and circumstances.

Background: The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product's actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication., Methods: We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials., Results: Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01-2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15-0.16)., Conclusions: Many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers.