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The investigational NEDD8‐activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single‐agent azacitidine in patients with higher‐risk myelodysplastic syndrome (higher‐risk MDS), higher‐risk chronic myelomonocytic leukemia (higher‐risk CMML), or low‐blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia‐inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug‐related and disease‐related intrinsic and extrinsic factors. A PubMed literature review (January 2000–November 2019) supported similarity in epidemiology of higher‐risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose‐escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug‐related and disease‐related intrinsic and extrinsic factors supported design of an Asia‐inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia‐inclusive MRCTs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Azacitidine is the standard of care for myelodysplastic syndromes/low‐blast acute myeloid leukemia (AML) across Western and East Asian patients. The first‐in‐class small‐molecule inhibitor of NEDD8‐activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS? By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian‐inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug‐related and disease‐related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These analyses provide scientific rationale for Asia‐inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia‐inclusive multiregional clinical trials.

To address the vast gap between current knowledge and practice in the area of dissemination and implementation research, we address terminology, provide examples of successful applications of this research, discuss key sources of support, and highlight directions and opportunities for future advances. There is a need for research testing approaches to scaling up and sustaining effective interventions, and we propose that further advances in the field will be achieved by focusing dissemination and implementation research on 5 core values: rigor and relevance, efficiency, collaboration, improved capacity, and cumulative knowledge.

[...]one recent study from Western Australia concluded that in 2010 the state population affected by a limited cohort of only 467 rare diseases represented 2% of the population but 10.5% of in‐patient hospital costs. [...]improved diagnostics and targeted therapeutics that keep these patients healthier and reduce their time in medical facilities would be highly beneficial. With the addition of new members, and in particular Japan in 2015, IRDiRC aims to capture data from specific geographic‐regulatory regions. [...]from 2017 onward, IRDiRC will be tracking approvals by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and more globally as other significant regulatory jurisdictions are added to the Consortium. Every successful gene discovery will not only unlock a potential diagnostic opportunity, but also has the potential to contribute to preventive and therapeutic opportunities for the corresponding rare disease, enabling precision medicine approaches for this patient population. [...]genetic linkages to rare diseases are extremely important and have incredible potential for rare disease patients. Other IRDiRC Task Forces include: i) the International Consortium of Human Phenotype Terminologies, which provided the community with standards to achieve interoperability between databases by enabling the linkage of phenotype and genotype databases for rare diseases ; ii) the Patient‐Centered Outcome Measures Task Force, which made recommendations on methods to support the development of patient‐relevant outcome measures for rare diseases in order to improve the quality of future trials and to provide data of relevance to the patient community ; iii) the Small Population Clinical Trials Task Force, which produced recommendations for efficient and innovative clinical trial designs relevant to small populations, often the focus of rare disease clinical trials, using scientific advice from regulators ; and iv) the Data Mining and Repurposing Task Force, which identified opportunities to leverage the existing research and patient data to realize the full potential of data mining and drug repurposing.

Background Understanding the mechanisms of implementation strategies (i.e., the processes by which strategies produce desired effects) is important for research to understand why a strategy did or did not achieve its intended effect, and it is important for practice to ensure strategies are designed and selected to directly target determinants or barriers. This study is a systematic review to characterize how mechanisms are conceptualized and measured, how they are studied and evaluated, and how much evidence exists for specific mechanisms. Methods We systematically searched PubMed and CINAHL Plus for implementation studies published between January 1990 and August 2018 that included the terms “mechanism,” “mediator,” or “moderator.” Two authors independently reviewed title and abstracts and then full texts for fit with our inclusion criteria of empirical studies of implementation in health care contexts. Authors extracted data regarding general study information, methods, results, and study design and mechanisms-specific information. Authors used the Mixed Methods Appraisal Tool to assess study quality. Results Search strategies produced 2277 articles, of which 183 were included for full text review. From these we included for data extraction 39 articles plus an additional seven articles were hand-entered from only other review of implementation mechanisms (total = 46 included articles). Most included studies employed quantitative methods (73.9%), while 10.9% were qualitative and 15.2% were mixed methods. Nine unique versions of models testing mechanisms emerged. Fifty-three percent of the studies met half or fewer of the quality indicators. The majority of studies (84.8%) only met three or fewer of the seven criteria stipulated for establishing mechanisms. Conclusions Researchers have undertaken a multitude of approaches to pursue mechanistic implementation research, but our review revealed substantive conceptual, methodological, and measurement issues that must be addressed in order to advance this critical research agenda. To move the field forward, there is need for greater precision to achieve conceptual clarity, attempts to generate testable hypotheses about how and why variables are related, and use of concrete behavioral indicators of proximal outcomes in the case of quantitative research and more directed inquiry in the case of qualitative research.

Background One of the most consistent findings from clinical and health services research is the failure to translate research into practice and policy. As a result of these evidence-practice and policy gaps, patients fail to benefit optimally from advances in healthcare and are exposed to unnecessary risks of iatrogenic harms, and healthcare systems are exposed to unnecessary expenditure resulting in significant opportunity costs. Over the last decade, there has been increasing international policy and research attention on how to reduce the evidence-practice and policy gap. In this paper, we summarise the current concepts and evidence to guide knowledge translation activities, defined as T2 research (the translation of new clinical knowledge into improved health). We structure the article around five key questions: what should be transferred; to whom should research knowledge be transferred; by whom should research knowledge be transferred; how should research knowledge be transferred; and, with what effect should research knowledge be transferred? Discussion We suggest that the basic unit of knowledge translation should usually be up-to-date systematic reviews or other syntheses of research findings. Knowledge translators need to identify the key messages for different target audiences and to fashion these in language and knowledge translation products that are easily assimilated by different audiences. The relative importance of knowledge translation to different target audiences will vary by the type of research and appropriate endpoints of knowledge translation may vary across different stakeholder groups. There are a large number of planned knowledge translation models, derived from different disciplinary, contextual ( i.e. , setting), and target audience viewpoints. Most of these suggest that planned knowledge translation for healthcare professionals and consumers is more likely to be successful if the choice of knowledge translation strategy is informed by an assessment of the likely barriers and facilitators. Although our evidence on the likely effectiveness of different strategies to overcome specific barriers remains incomplete, there is a range of informative systematic reviews of interventions aimed at healthcare professionals and consumers ( i.e. , patients, family members, and informal carers) and of factors important to research use by policy makers. Summary There is a substantial (if incomplete) evidence base to guide choice of knowledge translation activities targeting healthcare professionals and consumers. The evidence base on the effects of different knowledge translation approaches targeting healthcare policy makers and senior managers is much weaker but there are a profusion of innovative approaches that warrant further evaluation.

Background Little is known about how well or under what conditions health innovations are sustained and their gains maintained once they are put into practice. Implementation science typically focuses on uptake by early adopters of one healthcare innovation at a time. The later-stage challenges of scaling up and sustaining evidence-supported interventions receive too little attention. This project identifies the challenges associated with sustainability research and generates recommendations for accelerating and strengthening this work. Methods A multi-method, multi-stage approach, was used: (1) identifying and recruiting experts in sustainability as participants, (2) conducting research on sustainability using concept mapping, (3) action planning during an intensive working conference of sustainability experts to expand the concept mapping quantitative results, and (4) consolidating results into a set of recommendations for research, methodological advances, and infrastructure building to advance understanding of sustainability. Participants comprised researchers, funders, and leaders in health, mental health, and public health with shared interest in the sustainability of evidence-based health care. Results Prompted to identify important issues for sustainability research, participants generated 91 distinct statements, for which a concept mapping process produced 11 conceptually distinct clusters. During the conference, participants built upon the concept mapping clusters to generate recommendations for sustainability research. The recommendations fell into three domains: (1) pursue high priority research questions as a unified agenda on sustainability; (2) advance methods for sustainability research; (3) advance infrastructure to support sustainability research. Conclusions Implementation science needs to pursue later-stage translation research questions required for population impact. Priorities include conceptual consistency and operational clarity for measuring sustainability, developing evidence about the value of sustaining interventions over time, identifying correlates of sustainability along with strategies for sustaining evidence-supported interventions, advancing the theoretical base and research designs for sustainability research, and advancing the workforce capacity, research culture, and funding mechanisms for this important work.

Abstract Background Embedded research (ER) is recognized as one way to strengthen the integration of evidence into public health (PH) practice. In this paper, we outline a promising example of the co-production of research evidence between Fuse, the UKCRC Centre for Translational Research in Public Health and a local authority (LA) in north east England. Methods We critically examine attempts to share and use research findings to influence decision-making in a LA setting, drawing on insights from PH practitioners, managers, commissioners and academic partners involved in this organizational case study. We highlight what can be achieved as a co-located embedded researcher. Results The benefits and risks of ER are explored, alongside our reflections on the added value of this approach and the institutional prerequisites necessary for it to work. We argue that while this is not a new methodological approach, its application in PH as a way to facilitate evidence use is novel, and raises pragmatic and theoretical questions about the nature of impact and the extent to which it can be engineered. Conclusion With increased situated understanding of organizational culture and norms and greater awareness of the socio-political realities of PH, ER enables new co-produced solutions to become possible.

Background Integrated knowledge translation (IKT) refers to collaboration between researchers and decision-makers. While advocated as an approach for enhancing the relevance and use of research, IKT is challenging and inconsistently applied. This study sought to inform future IKT practice and research by synthesizing studies that empirically evaluated IKT and identifying knowledge gaps. Methods We performed a scoping review. We searched MEDLINE, EMBASE, and the Cochrane Library from 2005 to 2014 for English language studies that evaluated IKT interventions involving researchers and organizational or policy-level decision-makers. Data were extracted on study characteristics, IKT intervention (theory, content, mode, duration, frequency, personnel, participants, timing from initiation, initiator, source of funding, decision-maker involvement), and enablers, barriers, and outcomes reported by studies. We performed content analysis and reported summary statistics. Results Thirteen studies were eligible after screening 14,754 titles and reviewing 106 full-text studies. Details about IKT activities were poorly reported, and none were formally based on theory. Studies varied in the number and type of interactions between researchers and decision-makers; meetings were the most common format. All studies reported barriers and facilitators. Studies reported a range of positive and sub-optimal outcomes. Outcomes did not appear to be associated with initiator of the partnership, dedicated funding, partnership maturity, nature of decision-maker involvement, presence or absence of enablers or barriers, or the number of different IKT activities. Conclusions The IKT strategies that achieve beneficial outcomes remain unknown. We generated a summary of IKT approaches, enablers, barriers, conditions, and outcomes that can serve as the basis for a future review or for planning ongoing primary research. Future research can contribute to three identified knowledge gaps by examining (1) how different IKT strategies influence outcomes, (2) the relationship between the logic or theory underlying IKT interventions and beneficial outcomes, and (3) when and how decision-makers should be involved in the research process. Future IKT initiatives should more systematically plan and document their design and implementation, and evaluations should report the findings with sufficient detail to reveal how IKT was associated with outcomes.

Enormous progress has been made in the field of rheumatology in the past several decades, historically led by publicly funded academic innovators but in more recent times with much greater involvement of the pharmaceutical industry. This shift in resources has created a complex new model for reinvestment in the medical community in which the vast majority of private funds are redirected towards influencing the prescription behaviour of practitioners through ‘key opinion leaders’, with the main purpose of enhancing and perpetuating profit rather than innovation and critical thinking, and often at the expense of partnerships with scientists (that is, basic and translational researchers) and academic collaborations. This new episteme brings multiple opportunities to rethink approaches to sustaining long-term critical research in the field, ultimately maximizing the return on investment: scientific knowledge for the benefit of patients and society. Central to such strategies should be the rebalancing of academia–industry partnerships towards academic research and the involvement of ‘innovation and knowledge leaders’, rather than mostly key opinion leaders.In this article, the authors critically appraise the current model of opinion-based academia–industry interactions, and advocate for a realignment towards partnerships that foster innovation and knowledge.

Background Knowledge translation (KT) research in long-term care (LTC) is still in its early stages. This protocol describes the evaluation of a multifaceted, interdisciplinary KT intervention aimed at integrating evidence-based osteoporosis and fracture prevention strategies into LTC care processes. Methods and design The Vitamin D and Osteoporosis Study (ViD OS ) is underway in 40 LTC homes (n = 19 intervention, n = 21 control) across Ontario, Canada. The primary objectives of this study are to assess the feasibility of delivering the KT intervention, and clinically, to increase the percent of LTC residents prescribed ≥800 IU of vitamin D daily. Eligibility criteria are LTC homes that are serviced by our partner pharmacy provider and have more than one prescribing physician. The target audience within each LTC home is the Professional Advisory Committee (PAC), an interdisciplinary team who meets quarterly. The key elements of the intervention are three interactive educational sessions led by an expert opinion leader, action planning using a quality improvement cycle, audit and feedback reports, nominated internal champions, and reminders/point-of-care tools. Control homes do not receive any intervention, however both intervention and control homes received educational materials as part of the Ontario Osteoporosis Strategy. Primary outcomes are feasibility measures (recruitment, retention, attendance at educational sessions, action plan items identified and initiated, internal champions identified, performance reports provided and reviewed), and vitamin D (≥800 IU/daily) prescribing at 6 and 12 months. Secondary outcomes include the proportion of residents prescribed calcium supplements and osteoporosis medications, and falls and fractures. Qualitative methods will examine the experience of the LTC team with the KT intervention. Homes are centrally randomized to intervention and control groups in blocks of variable size using a computer generated allocation sequence. Randomization is stratified by home size and profit/nonprofit status. Prescribing data retrieval and analysis are performed by blinded personnel. Discussion Our study will contribute to an improved understanding of the feasibility and acceptability of a multifaceted intervention aimed at translating knowledge to LTC practitioners. Lessons learned from this study will be valuable in guiding future research and understanding the complexities of translating knowledge in LTC. Trial registration ClinicalTrials.gov NCT01398527.