The development and validation of the Discrimination and Stigma Scale Ultra Short for People Living with Dementia (DISCUS-Dementia).

BACKGROUND: The recent World Health Organization (WHO) blueprint for dementia research and Lancet Commission on ending stigma and discrimination in mental health has identified a gap around dementia-related measures of stigma and discrimination that can be used in different cultural, language and regional contexts. AIMS: We aimed to characterise experiences of discrimination, and report initial psychometric properties of a new tool to capture these experiences, among a global sample of people living with dementia. METHOD: We analysed data from 704 people living with dementia who took part in a global survey from 33 different countries and territories. Psychometric properties were examined, including internal consistency and construct validity. RESULTS: A total of 83% of participants reported discrimination in one or more areas of life, and this was similar across WHO Regions. The exploratory factor analysis factor loadings and scree plot supported a unidimensional structure for the Discrimination and Stigma Scale Ultra Short for People Living with Dementia (DISCUS-Dementia). The instrument demonstrated excellent internal consistency, with most of the construct validity hypotheses being confirmed and qualitative responses demonstrating face validity. CONCLUSIONS: Our analyses suggest that the DISCUS-Dementia performs well with a global sample of people living with dementia. This scale can be integrated into large-scale studies to understand factors associated with stigma and discrimination. It can also provide an opportunity for a structured discussion around stigma and discrimination experiences important to people living with dementia, as well as planning psychosocial services and initiatives to reduce stigma and discrimination.

Interface policies bridging outpatient and hospital sectors in Europe: can cross-sectorial collaboration in reimbursement and procurement improve access to affordable medicines?

INTRODUCTION: Pharmaceutical systems are frequently characterized by fragmentation, and competences for outpatient and inpatient sectors sit with different authorities, payers, and purchasers. This fragmentation of responsibilities can incentivize shifting expensive therapies and thus patients from one sector to the other. AREAS COVERED: Reimbursement and procurement policies in Europe addressing unwanted consequences of this fragmentation were identified through literature reviews and surveys with policy-makers. Good practice examples include cross-sectorial reimbursement lists managed by committees with representatives from the outpatient and hospital sectors, specific funding mechanisms, joint procurement involving purchasers from both sectors, actions against procurement contracts prohibiting generic competition, and an extension of Health Technology Assessment to the hospital sector. EXPERT OPINION: Recognizing fragmentation as a major challenge for pharmaceutical systems, policy-makers in some countries reacted by implementing policies to support cross-sectorial collaboration. However, only a handful of good practice examples exist for reimbursement and procurement policies in Europe. Though robust evaluations are lacking, there are indications that pharmaceutical policies which ensure collaboration at the interface of the outpatient and inpatient sectors would likely result in efficiency gains and better use of public budgets and may serve as lever to improve access to medicines.

In several European countries, the decision which medicines are funded by public money (reimbursement) and purchased by public institutions (public procurement) is taken independently for the outpatient sector and the hospital sector. There are different payers and procurers per sector, and even within a sector. Patients may be transferred between the sectors for financial reasons because one payer aims to shift the financial burden for the medication to the other sector.Policy-makers have understood the importance of better collaboration between the sectors, and some European countries introduced policies addressing the issue.The article presents examples of how reimbursement and procurement policies can be designed to improve the collaboration between the outpatient and hospital sectors. Committees that decide whether or not a medicine should be covered may contain representatives from both sectors; they may be mandated to take decisions that apply to medicines for outpatient use and administered in hospitals. Purchasers of both sectors may procure jointly a medicine. Supporting tools, such as the assessment of a medicine to support the decision on coverage and the price, may be used in both sectors. Financing solutions can reduce the incentive for one sector to shift a medicine to the other sector.These measures can help that patients gain improved access to affordable medicines. However, despite the introduction of such interface policies in some countries, policy-makers still need to continue working on overcoming the fragmentation in the pharmaceutical system.

Research evaluating the effectiveness of dementia interventions in low- and middle-income countries: A systematic mapping of 340 randomised controlled trials.

OBJECTIVES: More people with dementia live in low- and middle-income countries (LMICs) than in high-income countries, but best-practice care recommendations are often based on studies from high-income countries. We aimed to map the available evidence on dementia interventions in LMICs. METHODS: We systematically mapped available evidence on interventions that aimed to improve the lives of people with dementia or mild cognitive impairment (MCI) and/or their carers in LMICs (registered on PROSPERO: CRD42018106206). We included randomised controlled trials (RCTs) published between 2008 and 2018. We searched 11 electronic academic and grey literature databases (MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Global Health, World Health Organization Global Index Medicus, Virtual Health Library, Cochrane CENTRAL, Social Care Online, BASE, MODEM Toolkit) and examined the number and characteristics of RCTs according to intervention type. We used the Cochrane risk of bias 2.0 tool to assess the risk of bias. RESULTS: We included 340 RCTs with 29,882 (median, 68) participants, published 2008-2018. Over two-thirds of the studies were conducted in China (n = 237, 69.7%). Ten LMICs accounted for 95.9% of included RCTs. The largest category of interventions was Traditional Chinese Medicine (n = 149, 43.8%), followed by Western medicine pharmaceuticals (n = 109, 32.1%), supplements (n = 43, 12.6%), and structured therapeutic psychosocial interventions (n = 37, 10.9%). Overall risk of bias was judged to be high for 201 RCTs (59.1%), moderate for 136 (40.0%), and low for 3 (0.9%). CONCLUSIONS: Evidence-generation on interventions for people with dementia or MCI and/or their carers in LMICs is concentrated in just a few countries, with no RCTs reported in the vast majority of LMICs. The body of evidence is skewed towards selected interventions and overall subject to high risk of bias. There is a need for a more coordinated approach to robust evidence-generation for LMICs.

Accessing Dementia Care in Brazil: An Analysis of Case Vignettes.

BACKGROUND AND OBJECTIVES: Despite the rapid increase in the number of people living with dementia in Brazil, dementia care is limited. This study describes how people living with dementia and their carers access care, treatment, and support, and identifies what characteristics are likely to enable or prevent access. RESEARCH DESIGN AND METHODS: We created 10 vignettes to illustrate fictitious but realistic scenarios involving people living with dementia in Brazil. The vignettes explore a combination of socioeconomic and demographic variables. They were completed using an in-depth desk review of the dementia care landscape in Brazil; a Strengths, Opportunities, Weaknesses, and Threats (SWOT) analysis of the desk review; and expert knowledge. The analysis focused on identifying common sources of service provision, barriers of access to care and support, and specific issues experienced by some population groups. FINDINGS: Access to a dementia diagnosis, care, and support for people living with dementia in Brazil is limited. Demographic and socio-economic circumstances play a role in determining the type of services to which a person might have access. Poor knowledge about dementia, lack of capacity in the health system, and lack of formal long-term care support are among the identified barriers to accessing timely diagnosis, care, and support in the country. DISCUSSION AND IMPLICATIONS: Understanding the barriers and facilitators of access to diagnosis, treatment, and support for people with dementia and families with different demographic and socioeconomic characteristics is crucial for designing dementia policies that are context-specific and responsive to the care needs of different socioeconomic groups in Brazil.

Communication of anticancer drug benefits and related uncertainties to patients and clinicians: document analysis of regulated information on prescription drugs in Europe.

OBJECTIVE: To evaluate the frequency with which relevant and accurate information about the benefits and related uncertainties of anticancer drugs are communicated to patients and clinicians in regulated information sources in Europe. DESIGN: Document content analysis. SETTING: European Medicines Agency. PARTICIPANTS: Anticancer drugs granted a first marketing authorisation by the European Medicines Agency, 2017-19. MAIN OUTCOME MEASURES: Whether written information on a product addressed patients' commonly asked questions about: who and what the drug is used for; how the drug was studied; types of drug benefit expected; and the extent of weak, uncertain, or missing evidence for drug benefits. Information on drug benefits in written sources for clinicians (summaries of product characteristics), patients (patient information leaflets), and the public (public summaries) was compared with information reported in regulatory assessment documents (European public assessment reports). RESULTS: 29 anticancer drugs that received a first marketing authorisation for 32 separate cancer indications in 2017-19 were included. General information about the drug (including information on approved indications and how the drug works) was frequently reported across regulated information sources aimed at both clinicians and patients. Nearly all summaries of product characteristics communicated full information to clinicians about the number and design of the main studies, the control arm (if any), study sample size, and primary measures of drug benefit. None of the patient information leaflets communicated information to patients about how drugs were studied. 31 (97%) summaries of product characteristics and 25 (78%) public summaries contained information about drug benefits that was accurate and consistent with information in regulatory assessment documents. The presence or absence of evidence that a drug extended survival was reported in 23 (72%) summaries of product characteristics and four (13%) public summaries. None of the patient information leaflets communicated information about the drug benefits that patients might expect based on study findings. Scientific concerns about the reliability of evidence on drug benefits, which were raised by European regulatory assessors for almost all drugs in the study sample, were rarely communicated to clinicians, patients, or the public. CONCLUSIONS: The findings of this study highlight the need to improve the communication of the benefits and related uncertainties of anticancer drugs in regulated information sources in Europe to support evidence informed decision making by patients and their clinicians.

Post-Marketing Requirements for Cancer Drugs Approved by the European Medicines Agency, 2004-2014.

To address unresolved questions about drug safety and efficacy at the time of approval, the European Medicines Agency (EMA) may require that manufacturers conduct additional studies during the postmarketing period. As a growing proportion of new cancer drugs are approved on the basis of limited evidence of clinical benefit, timely completion of postmarketing requirements is important. We used publicly available regulatory documents to evaluate key characteristics of pivotal studies supporting EMA-approved cancer drugs from 2004-2014 and assessed completion rates of postmarketing data collection requirements after a minimum of 5 years. From 2004-2014, 79% (45/57) of EMA-approved cancer drugs had to fulfill postmarketing requirements. Pivotal trials supporting the approval of cancer drugs with postmarketing requirements were less likely to have randomized designs (41/61, 67% vs. 11/11, 100%), include an active comparator (20/61, 33% vs. 10/11, 91%), or measure overall survival as the primary study end point (18/61, 30% vs. 6/11, 55%) compared with pivotal trials for drugs without postmarketing requirements. Among 200 postmarketing requirements, almost half were designed to assess drug safety. After a minimum of 5 years, 60% (121/200) of requirements were completed, 10% (19/200) were ongoing, and 30% (60/200) were delayed. About half (40/75, 53%) of postmarketing requirements for new clinical studies were completed on time. Delays in the completion of postmarketing requirements often did not impact the likelihood of drugs receiving permanent marketing authorization (87%, 39/45) after 5 years. Our findings highlight the need for EMA to better enforce its authority to require timely completion of postmarketing requirements and studies.

Hemodynamic Changes During Physiological and Pharmacological Stress Testing in Patients With Heart Failure: A Systematic Review and Meta-Analysis.

Although disease etiologies differ, heart failure patients with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively) both present with clinical symptoms when under stress and impaired exercise capacity. The extent to which the adaptation of heart rate (HR), stroke volume (SV), and cardiac output (CO) under stress conditions is altered can be quantified by stress testing in conjunction with imaging methods and may help to detect the diminishment in a patient's condition early. The aim of this meta-analysis was to quantify hemodynamic changes during physiological and pharmacological stress testing in patients with HF. A systematic literature search (PROSPERO 2020:CRD42020161212) in MEDLINE was conducted to assess hemodynamic changes under dynamic and pharmacological stress testing at different stress intensities in HFpEF and HFrEF patients. Pooled mean changes were estimated using a random effects model. Altogether, 140 study arms with 7,248 exercise tests were analyzed. High-intensity dynamic stress testing represented 73% of these data (70 study arms with 5,318 exercise tests), where: HR increased by 45.69 bpm (95% CI 44.51-46.88; I 2 = 98.4%), SV by 13.49 ml (95% CI 6.87-20.10; I 2 = 68.5%), and CO by 3.41 L/min (95% CI 2.86-3.95; I 2 = 86.3%). No significant differences between HFrEF and HFpEF groups were found. Despite the limited availability of comparative studies, these reference values can help to estimate the expected hemodynamic responses in patients with HF. No differences in chronotropic reactions, changes in SV, or CO were found between HFrEF and HFpEF. When compared to healthy individuals, exercise tolerance, as well as associated HR and CO changes under moderate-high dynamic stress, was substantially impaired in both HF groups. This may contribute to a better disease understanding, future study planning, and patient-specific predictive models. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020161212].

Effectiveness of interventions for people living with dementia and their carers in Chinese communities: protocol for a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: As the largest and most rapidly ageing population, Chinese people are now the major driver of the continued growth in dementia prevalence globally. The need for evidence-based interventions in Chinese communities is urgent. Although a wide range of pharmacological and non-pharmacological interventions for dementia have been trialled in Chinese populations, the evidence has not been systematically synthesised. This systematic review and meta-analysis aims to map out the interventions for people living with dementia and their carers in Chinese communities worldwide and compare the effectiveness of these interventions. METHODS AND ANALYSIS: This protocol followed the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols checklist. We will search Chinese (China National Knowledge Infrastructure, WanFang DATA) and English bibliographical databases (MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Global Health, WHO Global Index Medicus, Virtual Health Library, Cochrane CENTRAL, Social Care Online, BASE, MODelling Outcome and cost impacts of interventions for DEMentia (MODEM) Toolkit, Cochrane Database of Systematic Reviews), complemented by hand searching of reference lists. We will include studies evaluating the effectiveness of interventions for dementia or mild cognitive impairment in Chinese populations, using a randomised controlled trial design, and published between January 2008 and June 2020. We will use a standardised form to extract data and Version 2 of the Cochrane risk-of-bias tool for randomised trials to assess the risk of bias of the included studies. Collected data will be fully interpreted with narrative synthesis and analysed using pairwise and network meta-analyses to pool intervention effects where sufficient information is available. We will perform subgroup analysis and meta-regression to explore potential reasons for heterogeneity. ETHICS AND DISSEMINATION: No formal ethics approval is required for this protocol. The findings will facilitate the development of studies on interventions for dementia and timely inform dementia policymaking and practice. Planned dissemination channels include peer-reviewed publications, conference presentations, public events and websites. PROSPERO REGISTRATION NUMBER: CRD42019134135.

The use of nonrandomized evidence to estimate treatment effects in health technology assessment.

Health technology assessment (HTA) is increasingly informed by nonrandomized studies, but there is limited guidance from HTA bodies on expectations around evidence quality and study conduct. We developed recommendations to support the appropriate use of such evidence based on a pragmatic literature review and a workshop involving 16 experts from eight countries as part of the EU's Horizon-2020 IMPACT-HTA program (work package six). To ensure HTA processes remain rigorous and robust, HTA bodies should demand clear, extensive and structured reporting of nonrandomized studies, including an in-depth assessment of the risk of bias. In recognition of the additional uncertainty imparted by nonrandomized designs in estimates of treatment effects, HTA bodies should strengthen early scientific advice and engage in collaborative efforts to improve use of real-world data.

Patient-reported outcome measures in core outcome sets targeted overlapping domains but through different instruments.

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.

Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment.

The COVID-19 pandemic is unlikely to end until there is global roll-out of vaccines that protect against severe disease and preferably drive herd immunity. Regulators in numerous countries have authorised or approved COVID-19 vaccines for human use, with more expected to be licensed in 2021. Yet having licensed vaccines is not enough to achieve global control of COVID-19: they also need to be produced at scale, priced affordably, allocated globally so that they are available where needed, and widely deployed in local communities. In this Health Policy paper, we review potential challenges to success in each of these dimensions and discuss policy implications. To guide our review, we developed a dashboard to highlight key characteristics of 26 leading vaccine candidates, including efficacy levels, dosing regimens, storage requirements, prices, production capacities in 2021, and stocks reserved for low-income and middle-income countries. We use a traffic-light system to signal the potential contributions of each candidate to achieving global vaccine immunity, highlighting important trade-offs that policy makers need to consider when developing and implementing vaccination programmes. Although specific datapoints are subject to change as the pandemic response progresses, the dashboard will continue to provide a useful lens through which to analyse the key issues affecting the use of COVID-19 vaccines. We also present original data from a 32-country survey (n=26 758) on potential acceptance of COVID-19 vaccines, conducted from October to December, 2020. Vaccine acceptance was highest in Vietnam (98%), India (91%), China (91%), Denmark (87%), and South Korea (87%), and lowest in Serbia (38%), Croatia (41%), France (44%), Lebanon (44%), and Paraguay (51%).

'Relative Consent' or 'Presumed Consent'? Organ donation attitudes and behaviour.

Legislation, in the form of presumed consent, has been argued to boost organ donation but most evidence disregards the practice of seeking relative's consent, which can either 'veto' donation decisions, or 'legitimize them', by removing any possible conflict with the donor's family. We study the effect of presumed consent alongside family consent on individuals' willingness to donate (WTD) one's own and relatives' organs, and on actual organ donation behaviours. Using data from 28 European countries for the period 2002-2010, we found that presumed consent (PC) policies are associated with increased willingness to donate organs, but this effect was attenuated once internal family discussions on organ donation were controlled for. Our findings indicate that relative's consent acts as a veto of donation intentions and attenuates the effect of regulation on actual donations. More specifically, PC increases WTD one's own and relatives' organs in countries where no family consent is required. Consistently, we find that family consent attenuates the influence of regulatory environment on actual donations. The effect is driven by the influence of family discussions which increased WTD, and in combination with presumed consent translated into higher organ donation rates.

Approval of Cancer Drugs With Uncertain Therapeutic Value: A Comparison of Regulatory Decisions in Europe and the United States.

Policy Points Regulatory agencies may have limited evidence on the clinical benefits and harms of new drugs when deciding whether new therapeutic agents are allowed to enter the market and under which conditions, including whether approval is granted under special regulatory pathways and obligations to address knowledge gaps through postmarketing studies are imposed. In a matched comparison of marketing applications for cancer drugs of uncertain therapeutic value reviewed by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), we found frequent discordance between the two agencies on regulatory outcomes and the use of special regulatory pathways. Both agencies often granted regular approval, even when the other agency judged there to be substantial uncertainty about drug benefits and risks that needed to be resolved through additional studies in the postmarketing period. Postmarketing studies imposed by regulators under special approval pathways to address remaining questions of efficacy and safety may not be suited to deliver timely, confirmatory evidence due to shortcomings in study design and delays, raising questions over the suitability of the FDA's Accelerated Approval and the EMA's Conditional Marketing Authorization as tools for allowing early market access for cancer drugs while maintaining rigorous regulatory standards. CONTEXT: Regulatory agencies are increasingly required to make market approval decisions for new drugs on the basis of limited clinical evidence, a situation commonly encountered in cancer. We aimed to investigate how regulators manage uncertainty in the benefit-risk profiles of new cancer drugs by comparing decisions for the world's two largest regulatory bodies-the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)-over a 5-year period. METHODS: We systematically identified a set of cancer drug-indication pairs for which data on efficacy and safety was less complete than that required for regular approval at time of market entry from 2009 to 2013, as determined by the FDA's use of Accelerated Approval (AA) or the EMA's use of Conditional Marketing Authorization (CMA) pathways, and matched these across the two agencies. Using publicly available information, we compared regulatory pathways and outcomes, final approved indications, and postmarketing obligations imposed by the agencies. FINDINGS: We identified 21 cancer drug-indication pairs that received FDA AA, EMA CMA, or both. Although most applications relied on identical pivotal trials across the FDA and the EMA, regulatory pathways often differed; 57% of indications received either FDA AA or EMA CMA, and regular approval by the other agency. After approval, the EMA more often accepted single-arm studies to confirm clinical benefit compared to the FDA (75% vs. 29% of indications), and the FDA more commonly requested randomized controlled trials (85% vs. 50%). Forty-one percent of confirmatory trials after FDA AA were conducted in different populations than the approved indication, compared to 13% after EMA CMA. Both agencies relied primarily on surrogate measures of patient benefit for postmarketing obligations. After a median follow-up of 7.25 years, 40% of FDA and 61% of EMA postmarketing obligations after AA and CMA, respectively, were delayed. CONCLUSIONS: US and European regulators often deemed early and less complete evidence on benefit-risk profiles of cancer drugs sufficient to grant regular approval, raising questions over regulatory standards for the approval of new medicines. Even when imposing confirmatory studies in the postmarketing period through special approval pathways, meaningful evidence may not materialize due to shortcomings in study design and delays in conducting required studies with due diligence.

Methods used in the selection of instruments for outcomes included in core outcome sets have improved since the publication of the COSMIN/COMET guideline.

OBJECTIVES: Once a core outcome set (COS) has been defined, it is important to achieve consensus on how these outcomes should be measured. The aims of this systematic review were to gain insight into the methods used to select outcome measurement instruments and to determine whether methods have improved following the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN)/Core Outcome Measures in Effectiveness Trials (COMET) guideline publication. STUDY DESIGN AND SETTING: Eligible articles, which were identified from the annual COMET systematic review, concerned any COS development studies that provided a recommendation on how to measure the outcomes included in the COS. Data were extracted on the methods used to select outcome measurement instruments in accordance with the COSMIN/COMET guideline. RESULTS: Of the 118 studies included in the review, 48% used more than one source of information when finding outcome measurement instruments, and 74% performed some form of quality assessment of the measurement instruments. Twenty-three studies recommended one single instrument for each core outcome included in the COS. Clinical experts and public representatives were involved in selecting instruments in 62% and 28% of studies, respectively. CONCLUSION: Methods used to select outcome measurement instruments have improved since the publication of the COSMIN/COMET guideline. Going forward, COS developers should ensure that recommended outcome measurement instruments have sufficient content validity. In addition, COS developers should recommend one instrument for each core outcome to contribute to the overarching goal of uniformity in outcome reporting.

Generating comparative evidence on new drugs and devices before approval.

Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.

A scoping review of core outcome sets and their 'mapping' onto real-world data using prostate cancer as a case study.

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.

Impact of predictive medicine on therapeutic decision making: a randomized controlled trial in congenital heart disease.

Computational modelling has made significant progress towards clinical application in recent years. In addition to providing detailed diagnostic data, these methods have the potential to simulate patient-specific interventions and to predict their outcome. Our objective was to evaluate to which extent patient-specific modelling influences treatment decisions in coarctation of the aorta (CoA), a common congenital heart disease. We selected three cases with CoA, two of which had borderline indications for intervention according to current clinical guidelines. The third case was not indicated for intervention according to guidelines. For each case, we generated two separate datasets. First dataset included conventional diagnostic parameters (echocardiography and magnetic resonance imaging). In the second, we added modelled parameters (pressure fields). For the two cases with borderline indications for intervention, the second dataset also included pressure fields after virtual stenting simulations. All parameters were computed by modelling methods that were previously validated. In an online-administered, invitation-only survey, we randomized 178 paediatric cardiologists to view either conventional (control) or add-on modelling (experimental) datasets. Primary endpoint was the proportion of participants recommending different therapeutic options: (1) surgery or catheter lab (collectively, "intervention") or (2) no intervention (follow-up with or without medication). Availability of data from computational predictive modelling influenced therapeutic decision making in two of three cases. There was a statistically significant association between group assignment and the recommendation of an intervention for one borderline case and one non-borderline case: 94.3% vs. 72.2% (RR: 1.31, 95% CI: 1.14-1.50, p = 0.00) and 18.8% vs. 5.1% (RR: 3.09, 95% CI: 1.17-8.18, p = 0.01) of participants in the experimental and control groups respectively recommended an intervention. For the remaining case, there was no difference between the experimental and control group and the majority of participants recommended intervention. In sub-group analyses, findings were not affected by the experience level of participating cardiologists. Despite existing clinical guidelines, the therapy recommendations of the participating physicians were heterogeneous. Validated patient-specific computational modelling has the potential to influence treatment decisions. Future studies in broader areas are needed to evaluate whether differences in decisions result in improved outcomes (Trial Registration: NCT02700737).