European Network for Health Technology Assessment's Response to COVID-19: Rapid Collaborative Reviews on Diagnostic Tests and Rolling and Rapid Collaborative Reviews on Therapeutics.

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

Synthesizing quantitative and qualitative information on multiple comparisons of health interventions to facilitate knowledge transfer: an example from an EUnetHTA multi-HTA.

OBJECTIVE: Presenting an approach to synthesize quantitative and qualitative information from systematic reviews of multiple health interventions. METHODS: Within the context of an EUnetHTA multi-health technology assessment of twenty-three surgical techniques, we developed synthetic single tables, using color gradients and abbreviations, with information on which technologies had been compared, estimates of the size of differences for available comparisons, their clinical relevance, and certainty of the related evidence. RESULTS: The proposed methodology provided, through a single depiction, information normally included in multiple figures/tables such as network plots, league tables, and summary of findings tables. CONCLUSION: Transferring information on benefits, risks, and certainty of the available evidence on health interventions may be challenging, especially when assessing multiple treatments: more pieces of information need to be integrated in order to show an overall picture for each of the chosen outcomes, and usual reporting tools may be targeted to researchers more than to different kinds of decision makers. While more in-depth layers of information can always be added to satisfy needs of different audiences, the proposed tools could favor a quick interpretation of articulated scientific data by both decision makers and researchers.

Hadrontherapy for cancer. An overview of HTA reports and ongoing studies

Introduction: There is growing interest in the use of both proton beam therapy (PBT) and carbon ion radiation therapy (CIRT), which are types of hadrontherapy. Although neither are new technologies they have been subject to assessment by several Health Technology Assessment (HTA) agencies over the past years. The main claimed benefit of PBT and CIRT is a reduction in toxicity compared to conventional radiation therapy, resulting in fewer harms and a lower risk of induced secondary malignancies. Such an advantage would be particularly relevant to children and young adults. Sizeable hadrontherapy centres expansion is underway worldwide, while evidence supporting claims of superiority over conventional radiation therapy is thought to be currently insufficient. Objectives: The report is aimed at presenting the state of the art of clinical research in both PBT and CIRT, by summarising the evidence findings from most recent and uptodate HTA reports and by providing a description of all currently ongoing clinical studies. Methods: The search for HTA reports was carried out on 3 databases to identify reports published between January 2011 and June 2019. The quality of the identified reports was assessed using the AMSTAR instrument. The search for ongoing studies was carried out on four public registers in July 2019. All identified ongoing studies were included. Results: The overview of available evidence for PBT is drawn from five HTA reports on a total of 16 oncology indications, including 295 primary studies of any study design. One HTA report also included eight guidelines. All included HTA reports concluded that the quality of research is low and that there is insufficient evidence to support the claimed benefits of PBT. Seventytwo non-comparative ongoing studies and 25 comparative ongoing studies were identified. Seventeen were randomized controlled studies comparing Proton Beam Therapy with current practice. The search for HTA reports assessing the use of CIRT in oncology identified five reports, two of which were up to date and of good quality reporting data from primary studies. The largest report identified 56 studies on 13 indications, but only 27 studies (including only one randomised trial) could be included in a qualitative synthesis, providing no evidence of differences in efficacy and safety of CIRT compared to photontherapy. The other report focused on the effects of CIRT on chordomas and chondrosarcomas, highlighting the heterogeneity and inconsistency of available data mostly coming from low-quality studies. Thirtyseven ongoing studies were identified, 5 of which were RCT versus conventional treatment and 32 were single-arm studies. Table A summarises the findings, by clinical indication, from the included HTA reports and from the overview of ongoing clinical research. The Table reports the current level of certainty on superiority of PBT or CIRT compared to photon radiation therapy and the likelihood that future research results would resolve current uncertainty. Conclusions. Despite the growing number of studies being published and the growing number of PBT and/or CIRT centres opening or at a planning stage, there is persistent uncertainty on the added clinical benefit of hadrontherapy treatments over conventional radiation therapy. Clinical research currently underway may not contribute to solve this uncertainty. There is a lack of agreement on the appropriate study design to assess the effects of hadrontherapies and lack of coordination between centres in the production of joint research protocols to generate the necessary evidence. This has led to the production of numerous small, poorly designed and reported studies. These shortcomings might confine the use of PBT and CIRT to experimental treatments and require that patients willing to undergo PBT or CIRT be fully informed of the risks and uncertainties of the outcomes.

Lifestyle-tailored interventions for South Asians with type 2 diabetes living in high-income countries: a systematic review.

AIM: To summarize evidence on the effectiveness of educational interventions for type 2 diabetes control in South Asians living in high-income countries. METHODS: We systematically searched PubMed, EMBASE, Cinahl and the Cochrane Library, using Medical Subject Heading and free-text terms. The considered outcomes were: mortality, morbidity, glycaemic control, blood pressure, practice (diet, physical activity and self-care), attitudes/awareness and knowledge. Papers published up to July 2015 were considered. Two reviewers independently screened the title and abstract and then read the full text of selected papers. RESULTS: Nine studies were included, four non-randomized studies of interventions and five randomized controlled trials. All studies except one were conducted in the UK. Target population ranged from 39 to 1486 individuals; the follow-up ranged from 1 to 24 months. The interventions were mostly based on a tailored educational package, individually or group administered, conducted by lay link workers, health professionals or both. No study measured mortality or morbidity. An effect on glycaemic control was observed only in before/after studies, while a randomized study showed a non-significant improvement (percentage of glycated haemoglobin -0.15, P = 0.11). Two randomized studies found a reduction in blood pressure. Changes in practice and attitudes showed heterogeneous results, mostly favouring intervention. CONCLUSIONS: There was weak evidence that interventions using link workers and tailored education can modify attitudes, self-care skills and blood pressure in South Asian migrants to industrialized countries. Only one larger trial, with adequate follow-up, showed a small non-significant improvement of glycaemic control.

Interventions to reduce waiting times for elective procedures.

BACKGROUND: Long waiting times for elective healthcare procedures may cause distress among patients, may have adverse health consequences and may be perceived as inappropriate delivery and planning of health care. OBJECTIVES: To assess the effectiveness of interventions aimed at reducing waiting times for elective care, both diagnostic and therapeutic. SEARCH METHODS: We searched the following electronic databases: Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946-), EMBASE (1947-), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), ABI Inform, the Canadian Research Index, the Science, Social Sciences and Humanities Citation Indexes, a series of databases via Proquest: Dissertations & Theses (including UK & Ireland), EconLit, PAIS (Public Affairs International), Political Science Collection, Nursing Collection, Sociological Abstracts, Social Services Abstracts and Worldwide Political Science Abstracts. We sought related reviews by searching the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effectiveness (DARE). We searched trial registries, as well as grey literature sites and reference lists of relevant articles. SELECTION CRITERIA: We considered randomised controlled trials (RCTs), controlled before-after studies (CBAs) and interrupted time series (ITS) designs that met EPOC minimum criteria and evaluated the effectiveness of any intervention aimed at reducing waiting times for any type of elective procedure. We considered studies reporting one or more of the following outcomes: number or proportion of participants whose waiting times were above or below a specific time threshold, or participants' mean or median waiting times. Comparators could include any type of active intervention or standard practice. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from, and assessed risk of bias of, each included study, using a standardised form and the EPOC 'Risk of bias' tool. They classified interventions as follows: interventions aimed at (1) rationing and/or prioritising demand, (2) expanding capacity, or (3) restructuring the intake assessment/referral process.For RCTs when available, we reported preintervention and postintervention values of outcome for intervention and control groups, and we calculated the absolute change from baseline or the effect size with 95% confidence interval (CI). We reanalysed ITS studies that had been inappropriately analysed using segmented time-series regression, and obtained estimates for regression coefficients corresponding to two standardised effect sizes: change in level and change in slope. MAIN RESULTS: Eight studies met our inclusion criteria: three RCTs and five ITS studies involving a total of 135 general practices/primary care clinics, seven hospitals and one outpatient clinic. The studies were heterogeneous in terms of types of interventions, elective procedures and clinical conditions; this made meta-analysis unfeasible.One ITS study evaluating prioritisation of demand through a system for streamlining elective surgery services reduced the number of semi-urgent participants waiting longer than the recommended time (< 90 days) by 28 participants/mo, while no effects were found for urgent (< 30 days) versus non-urgent participants (< 365 days).Interventions aimed at restructuring the intake assessment/referral process were evaluated in seven studies. Four studies (two RCTs and two ITSs) evaluated open access, or direct booking/referral: One RCT, which showed that open access to laparoscopic sterilisation reduced waiting times, had very high attrition (87%); the other RCT showed that open access to investigative services reduced waiting times (30%) for participants with lower urinary tract syndrome (LUTS) but had no effect on waiting times for participants with microscopic haematuria. In one ITS study, same-day scheduling for paediatric health clinic appointments reduced waiting times (direct reduction of 25.2 days, and thereafter a decrease of 3.03 days per month), while another ITS study showed no effect of a direct booking system on proportions of participants receiving a colposcopy appointment within the recommended time. One RCT and one ITS showed no effect of distant consultancy (instant photography for dermatological conditions and telemedicine for ear nose throat (ENT) conditions) on waiting times; another ITS study showed no effect of a pooled waiting list on the number of participants waiting for uncomplicated spinal surgery.Overall quality of the evidence for all outcomes, assessed using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) tool, ranged from low to very low.We found no studies evaluating interventions to increase capacity or to ration demand. AUTHORS' CONCLUSIONS: As only a handful of low-quality studies are presently available, we cannot draw any firm conclusions about the effectiveness of the evaluated interventions in reducing waiting times. However, interventions involving the provision of more accessible services (open access or direct booking/referral) show some promise.

A qualitative systematic review of studies using the normalization process theory to research implementation processes.

BACKGROUND: There is a well-recognized need for greater use of theory to address research translational gaps. Normalization Process Theory (NPT) provides a set of sociological tools to understand and explain the social processes through which new or modified practices of thinking, enacting, and organizing work are implemented, embedded, and integrated in healthcare and other organizational settings. This review of NPT offers readers the opportunity to observe how, and in what areas, a particular theoretical approach to implementation is being used. In this article we review the literature on NPT in order to understand what interventions NPT is being used to analyze, how NPT is being operationalized, and the reported benefits, if any, of using NPT. METHODS: Using a framework analysis approach, we conducted a qualitative systematic review of peer-reviewed literature using NPT. We searched 12 electronic databases and all citations linked to six key NPT development papers. Grey literature/unpublished studies were not sought. Limitations of English language, healthcare setting and year of publication 2006 to June 2012 were set. RESULTS: Twenty-nine articles met the inclusion criteria; in the main, NPT is being applied to qualitatively analyze a diverse range of complex interventions, many beyond its original field of e-health and telehealth. The NPT constructs have high stability across settings and, notwithstanding challenges in applying NPT in terms of managing overlaps between constructs, there is evidence that it is a beneficial heuristic device to explain and guide implementation processes. CONCLUSIONS: NPT offers a generalizable framework that can be applied across contexts with opportunities for incremental knowledge gain over time and an explicit framework for analysis, which can explain and potentially shape implementation processes. This is the first review of NPT in use and it generates an impetus for further and extended use of NPT. We recommend that in future NPT research, authors should explicate their rationale for choosing NPT as their theoretical framework and, where possible, involve multiple stakeholders including service users to enable analysis of implementation from a range of perspectives.

Evaluating complex interventions and health technologies using normalization process theory: development of a simplified approach and web-enabled toolkit.

BACKGROUND: Normalization Process Theory (NPT) can be used to explain implementation processes in health care relating to new technologies and complex interventions. This paper describes the processes by which we developed a simplified version of NPT for use by clinicians, managers, and policy makers, and which could be embedded in a web-enabled toolkit and on-line users manual. METHODS: Between 2006 and 2010 we undertook four tasks. (i) We presented NPT to potential and actual users in multiple workshops, seminars, and presentations. (ii) Using what we discovered from these meetings, we decided to create a simplified set of statements and explanations expressing core constructs of the theory (iii) We circulated these statements to a criterion sample of 60 researchers, clinicians and others, using SurveyMonkey to collect qualitative textual data about their criticisms of the statements. (iv) We then reconstructed the statements and explanations to meet users' criticisms, embedded them in a web-enabled toolkit, and beta tested this 'in the wild'. RESULTS: On-line data collection was effective: over a four week period 50/60 participants responded using SurveyMonkey (40/60) or direct phone and email contact (10/60). An additional nine responses were received from people who had been sent the SurveyMonkey form by other respondents. Beta testing of the web enabled toolkit produced 13 responses, from 327 visits to http://www.normalizationprocess.org. Qualitative analysis of both sets of responses showed a high level of support for the statements but also showed that some statements poorly expressed their underlying constructs or overlapped with others. These were rewritten to take account of users' criticisms and then embedded in a web-enabled toolkit. As a result we were able translate the core constructs into a simplified set of statements that could be utilized by non-experts. CONCLUSION: Normalization Process Theory has been developed through transparent procedures at each stage of its life. The theory has been shown to be sufficiently robust to merit formal testing. This project has provided a user friendly version of NPT that can be embedded in a web-enabled toolkit and used as a heuristic device to think through implementation and integration problems.

Normalisation process theory: a framework for developing, evaluating and implementing complex interventions.

BACKGROUND: The past decade has seen considerable interest in the development and evaluation of complex interventions to improve health. Such interventions can only have a significant impact on health and health care if they are shown to be effective when tested, are capable of being widely implemented and can be normalised into routine practice. To date, there is still a problematic gap between research and implementation. The Normalisation Process Theory (NPT) addresses the factors needed for successful implementation and integration of interventions into routine work (normalisation). DISCUSSION: In this paper, we suggest that the NPT can act as a sensitising tool, enabling researchers to think through issues of implementation while designing a complex intervention and its evaluation. The need to ensure trial procedures that are feasible and compatible with clinical practice is not limited to trials of complex interventions, and NPT may improve trial design by highlighting potential problems with recruitment or data collection, as well as ensuring the intervention has good implementation potential. SUMMARY: The NPT is a new theory which offers trialists a consistent framework that can be used to describe, assess and enhance implementation potential. We encourage trialists to consider using it in their next trial.

A method for addressing research gaps in HTA, developed whilst evaluating robotic-assisted surgery: a proposal.

BACKGROUND: When evaluating health technologies with insufficient scientific evidence, only innovative potentials can be assessed. A Regional policy initiative linking the governance of health innovations to the development of clinical research has been launched by the Region of Emilia Romagna Healthcare Authority. This program, aimed at enhancing the research capacity of health organizations, encourages the development of adoption plans that combine use in clinical practice along with experimental use producing better knowledge. Following the launch of this program we developed and propose a method that, by evaluating and ranking scientific uncertainty, identifies the moment (during the stages of the technology's development) where it would be sensible to invest in research resources and capacity to further its evaluation. The method was developed and tested during a research project evaluating robotic surgery. METHODS: A multidisciplinary panel carried out a 5-step evaluation process: 1) definition of the technology's evidence profile and of all relevant clinical outcomes; 2) systematic review of scientific literature and outline of the uncertainty profile differentiating research results into steady, plausible, uncertain and unknown results; 3) definition of the acceptable level of uncertainty for investing research resources; 4) analysis of local context; 5) identification of clinical indications with promising clinical return. RESULTS: Outputs for each step of the evaluation process are: 1) evidence profile of the technology and systematic review; 2) uncertainty profile for each clinical indication; 3) exclusion of clinical indications not fulfilling the criteria of maximum acceptable risk; 4) mapping of local context; 5) recommendations for research.Outputs of the evaluation process for robotic surgery are described in the paper. CONCLUSIONS: This method attempts to rank levels of uncertainty in order to distinguish promising from hazardous clinical use and to outline a research course of action. Decision makers wishing to tie coverage policies to the development of scientific evidence could find this method a useful aid to the governance of innovations.

Development of a theory of implementation and integration: Normalization Process Theory.

BACKGROUND: Theories are important tools in the social and natural sciences. The methods by which they are derived are rarely described and discussed. Normalization Process Theory explains how new technologies, ways of acting, and ways of working become routinely embedded in everyday practice, and has applications in the study of implementation processes. This paper describes the process by which it was built. METHODS: Between 1998 and 2008, we developed a theory. We derived a set of empirical generalizations from analysis of data collected in qualitative studies of healthcare work and organization. We developed an applied theoretical model through analysis of empirical generalizations. Finally, we built a formal theory through a process of extension and implication analysis of the applied theoretical model. RESULTS: Each phase of theory development showed that the constructs of the theory did not conflict with each other, had explanatory power, and possessed sufficient robustness for formal testing. As the theory developed, its scope expanded from a set of observed regularities in data with procedural explanations, to an applied theoretical model, to a formal middle-range theory. CONCLUSION: Normalization Process Theory has been developed through procedures that were properly sceptical and critical, and which were opened to review at each stage of development. The theory has been shown to merit formal testing.

CoCanCPG. Coordination of cancer clinical practice in Europe.

All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, stepwise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to setting up transnational collaboration. Through its activities, CoCanCPG will make an important contribution towards better access to evidence-based cancer practices and thus contribute to reducing inequalities and improving care for patients with cancer across Europe.

Understanding the implementation of complex interventions in health care: the normalization process model.

BACKGROUND: The Normalization Process Model is a theoretical model that assists in explaining the processes by which complex interventions become routinely embedded in health care practice. It offers a framework for process evaluation and also for comparative studies of complex interventions. It focuses on the factors that promote or inhibit the routine embedding of complex interventions in health care practice. METHODS: A formal theory structure is used to define the model, and its internal causal relations and mechanisms. The model is broken down to show that it is consistent and adequate in generating accurate description, systematic explanation, and the production of rational knowledge claims about the workability and integration of complex interventions. RESULTS: The model explains the normalization of complex interventions by reference to four factors demonstrated to promote or inhibit the operationalization and embedding of complex interventions (interactional workability, relational integration, skill-set workability, and contextual integration). CONCLUSION: The model is consistent and adequate. Repeated calls for theoretically sound process evaluations in randomized controlled trials of complex interventions, and policy-makers who call for a proper understanding of implementation processes, emphasize the value of conceptual tools like the Normalization Process Model.

Implementing guidelines for venous thromboembolism prophylaxis in a large Italian teaching hospital: lights and shadows.

BACKGROUND AND OBJECTIVES: Venous thromboembolism (VTE) remains a serious complication in hospitalized patients, in spite of several published guidelines (GL) on its prevention. The objective of this study (part of the TRiPSS-2 project) was to evaluate the impact of a locally adapted GL, supported by a multifaceted implementation strategy, in improving VTE prophylaxis in a large teaching hospital. DESIGN AND METHODS: A before and after controlled study was used to evaluate the impact of the recommendations on the appropriateness of prophylaxis. We evaluated the medical charts of two random samples, each of 250 patients, discharged in the first semester of the years 2000 and 2002. The hospital incidence of VTE (1996-2004) was also monitored, through the discharge summaries. RESULTS: Among high risk patients, appropriateness of prophylaxis increased both in medical (from 25% to 41.7%, p=0.0075) and in surgical patients (from 63.7% to 97.1%, p=0.0004). A parallel sharp increase (by 6-8 times) of consumption of elastic stockings was documented. In both medical and surgical patients the incidence of VTE decreased markedly and sustainedly in 2002-2004, with an adjusted odds ratio of 0.68 (95% confidence interval: 0.62-0.75). However, the use of lower than recommended doses of heparins and the increased use of prophylaxis in low risk patients represent unsolved problems. INTERPRETATION AND CONCLUSIONS: Implementing locally adapted GL may be highly effective in improving appropriateness of prophylaxis and in reducing the incidence of VTE; however a careful evaluation of changes is recommended in order to identify unsolved problems or undesired effects.